ARDC Research Link Australia

Publication

Publisher: Elsevier BV

Date: 10-2017

DOI: 10.1016/J.NMD.2017.06.288

Publication

Sporadic inclusion body myositis in Japanese is associated with the MHC ancestral haplotype 52.1

Publisher: Elsevier BV

Date: 05-2006

DOI: 10.1016/J.NMD.2006.02.002

Abstract: In Caucasians, sporadic inclusion body myositis has been associated with the MHC ancestral haplotypes HLA-A1, B8, DR3 (8.1AH) and HLA-B35, DR1 (35.2AH). It is not known whether these haplotypes carry susceptibility for the disease in other ethnic groups. We report here the results of HLA-B and -DRB1 typing using a high-resolution sequence-based technique in a cohort of 31 Japanese patients with definite sIBM. Patient allele frequencies were 40.3% for HLA-B*5201 (10.7% in controls: p<0.001) and 37.1% for HLA-DRB1*1502 (10% in controls: p<0.001). Both alleles were found together as part of a conserved haplotype (52.1AH) at a frequency of 37.1% in patients (8.4% in controls: p<0.001). This is the first description of a haplotypic MHC association with sporadic inclusion body myositis in Japanese patients. These findings indicate that different MHC ancestral haplotypes are associated with sIBM in different ethnic groups and further emphasize the importance of genetic factors in this condition.

Publication

TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype

Publisher: Wiley

Date: 13-11-2015

DOI: 10.1002/ANA.24535

Publication

Clinical utility gene card for: Nemaline myopathy

Publisher: Springer Science and Business Media LLC

Date: 18-04-2012

DOI: 10.1038/EJHG.2012.70

Publication

Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene

Publisher: Elsevier BV

Date: 02-2003

DOI: 10.1016/S0960-8966(02)00218-3

Abstract: The congenital myopathies are a group of disorders characterised by the predominance of specific histological features observed in biopsied muscle. Central core disease and nemaline myopathy are ex les of congenital myopathies that have specific histological characteristics but significantly overlapping clinical pictures. Central core disease is an autosomal dominant disorder with variable penetrance which has been linked principally to the gene for the skeletal muscle calcium release channel (RYR1). Two recent reports have identified the 3' transmembrane domain of this gene as a common site for mutations. Two other studies have reported single families that have features of both central core disease and nemaline myopathy (core/rod disease) caused by mutations in RYR1. Screening of the 3' region (exons 93-105) of the RYR1 gene for mutations in 27 apparently unrelated patients with either central core disease or core/rod disease by single strand conformation polymorphism analysis and DNA sequencing identified three described and nine novel mutations in 15 patients.

Publication

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 21-03-2012

DOI: 10.1212/WNL.0B013E31824E8EBE

Publication

Myosin storage (hyaline body) myopathy: A case report

Publisher: Elsevier BV

Date: 12-2006

DOI: 10.1016/J.NMD.2006.09.001

Abstract: Myosin storage myopathy/hyaline body myopathy is a rare congenital myopathy, with less than 30 cases reported in the literature. It is characterised by the presence of subsarcolemmal hyaline bodies in type 1 muscle fibres and predominantly proximal muscle weakness. Recently, a single mutation (Arg1845Trp) in the slow/beta-cardiac myosin heavy chain gene (MYH7) was identified in four unrelated probands from Sweden and Belgium. The clinical severity and age of onset was variable, despite the same disease-causing mutation and similar histological findings. Here, we report the clinical and morphological findings of two brothers of English/Scottish background with the Arg1845Trp mutation in MYH7. This case report adds to the clinical description of this rare disorder and confirms that Arg1845Trp is a common mutation associated with this phenotype, at least in the White European population.

Publication

Actin myopathy with nemaline bodies, intranuclear rods, and a heterozygous mutation in ACTA1 (Asp154Asn)

Publisher: Springer Science and Business Media LLC

Date: 24-06-2004

DOI: 10.1007/S00401-004-0888-1

Abstract: Mutations in the skeletal muscle alpha-actin gene ( ACTA1) are associated by and large with three muscle diseases (1) congenital actin myopathy, (2) nemaline myopathy, and (3) intranuclear rod myopathy. More than 70 mutations have now been identified. The majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The present case, a boy of healthy Turkish parents, had a severe form of the disease of the latter type due to a heterozygous, presumably de novo mutation of the ACTA1 gene in exon 4 (Asp154Asn), with lack of spontaneous movements at birth requiring immediate mechanical ventilation. He died at the age of 9 weeks due to respiratory failure, secondary pneumonia, and chylothorax. The biopsy specimen of the femoral muscle was characterized by pleomorphic alterations with numerous muscle fibers showing accumulation of actin filaments, but, in addition, both nemaline bodies and intranuclear rod bodies. This was also seen in several other muscles investigated at autopsy. No developmental abnormalities of the central nervous system, and no loss of spinal motor neurons were detected despite atrophy or hypotrophy of a considerable number of muscle fibers. The peripheral nervous system, which has not been studied before in patients with ACTA1 mutations, showed no loss of motor or sensory myelinated fibers and no loss of sensory neurons in spinal ganglia.

Publication

Allelic loss of cyclophilin 40, an estrogen receptor-associated immunophilin, in breast carcinomas

Publisher: Springer Science and Business Media LLC

Date: 22-01-2001

DOI: 10.1007/S004320000182

Abstract: Cyclophilin 40 (CyP40) is an estrogen receptor-associated protein which appears to modify receptor function. The aim of this study was to determine the extent of allelic loss at the CyP40 locus in a panel of breast carcinomas using a newly characterized microsatellite marker located upstream of the CyP40 gene and then to correlate this with losses at chromosomal sites for cancer-associated genes. Allelic loss at CyP40 was determined from patients' matched tumor and normal breast tissue using Genescan 672 software analysis of fluorescently labeled, PAGE-separated PCR products incorporating the marker. For each patient, allelic loss at CyP40 was then assessed and compared with losses at markers for various cancer-associated genes. Allelic loss was detected in 30% of breast carcinomas from patients heterozygous for the CyP40 marker. All carcinomas demonstrating allelic loss were grade II or III invasive ductal carcinomas and generally showed multiple losses at other sites near known cancer-associated genes. The polymorphic marker which we characterized was useful in determining allelic loss at the CyP40 locus in breast cancer patients and when applied in these studies in conjunction with various cancer-associated gene markers, suggests that deletions in the region of the CyP40 gene might be a late event in breast tumor progression.

Publication

Distal arthrogryposis type 5D with novel clinical features and compound heterozygous mutations in ECEL1

Publisher: Wiley

Date: 29-04-2014

DOI: 10.1002/AJMG.A.36342

Publication

Diagnosis of fetal akinesia and arthrogryposis by panel sequencing and functional genomics

Publisher: Elsevier BV

Date: 10-2019

DOI: 10.1016/J.NMD.2019.06.296

Publication

Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies

Publisher: Wiley

Date: 26-03-2018

DOI: 10.1111/ENE.13607

Abstract: Nemaline myopathy (NEM) has been associated with mutations in 12 genes to date. However, for some patients diagnosed with NEM, definitive mutations are not identified in the known genes, suggesting that there are other genes involved. This study describes compound heterozygosity for rare variants in ryanodine receptor type 3 (RYR3) gene in one such patient. Clinical examination of the patient at 22 years of age revealed a long narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear and subsarcolemmal areas, and within the cytoplasm. No likely pathogenic mutations in known NEM genes were identified. Copy number variation in known NEM genes was excluded by NEM-targeted comparative genomic hybridization array. Next-generation sequencing revealed compound heterozygous missense variants in the RYR3 gene. RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain and cauda equina s les. Immunofluorescence of human skeletal muscle revealed a 'single-row' appearance of RYR3, interspersed between the 'double rows' of ryanodine receptor type 1 (RYR1) at each A-I junction. The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain, and the subcellular localization of RYR1 and RYR3 in human skeletal muscle.

Publication

Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2

Publisher: Elsevier BV

Date: 03-2018

DOI: 10.1016/J.AJHG.2018.01.023

Publication

Correspondence on “Screening for autosomal recessive and X-linked conditions during pregnancy and preconception

Publisher: Elsevier BV

Date: 05-2022

DOI: 10.1016/J.GIM.2022.01.007

Publication

Nemaline myopathy caused by absence of α-skeletal muscle actin

Publisher: Wiley

Date: 02-2007

DOI: 10.1002/ANA.21035

Abstract: To investigate seven congenital myopathy patients from six families: one French Gypsy, one Spanish Gypsy, four British Pakistanis, and one British Indian. Three patients required mechanical ventilation from birth, five died before 22 months, one is ventilator-dependent, but one, at 30 months, is sitting with minimal support. All parents were unaffected. The alpha-skeletal muscle actin gene (ACTA1) was sequenced. Available muscle biopsies were investigated by standard histological and electron microscopic techniques. The expression of various proteins was determined by immunohistochemistry, western blotting, or both. Three homozygous ACTA1 null mutations were identified: p.Arg41X in the French patient, p.Tyr364fsX in the Spanish patient, and p.Asp181fsX10 in all five British patients. An absence of alpha-skeletal muscle actin protein but presence of alpha-cardiac actin was shown in all muscle biopsies examined, with more alpha-cardiac actin in the biopsy from the child with the greatest muscle function. Muscle biopsies from all patients exhibited nemaline bodies whereas three also contained zebra bodies. The seven patients have recessive nemaline myopathy caused by absence of alpha-skeletal muscle actin. The level of retention of alpha-cardiac actin, the skeletal muscle fetal actin isoform, may determine alpha-skeletal muscle actin disease severity. This has implications for possible future therapy.

Publication

Nemaline Myopathy with Minicores Caused by Mutation of the CFL2 Gene Encoding the Skeletal Muscle Actin–Binding Protein, Cofilin-2

Publisher: Elsevier BV

Date: 2007

DOI: 10.1086/510402

Publication

Publisher: Hindawi Limited

Date: 17-05-2022

DOI: 10.1002/HUMU.24393

Publication

Genetic neuromuscular disorders: what is the best that we can do?

Publisher: Elsevier BV

Date: 10-2021

DOI: 10.1016/J.NMD.2021.07.007

Abstract: The major advances in genetic neuromuscular disorders in the last 30 years have been: (a) identification of the genetic basis for hundreds of these disorders, (b) through knowing the genes, understanding their pathobiology and (c) subsequent implementation of evidence-based treatments for some of the disorders. New genomic technologies are providing precision diagnosis, mode of inheritance and likely prognosis for more patients than ever before. Parents of children with a genetic diagnosis can then use preimplantation or prenatal diagnosis to avoid having further affected children if they wish. But is this the best we can do for genetic neuromuscular disorders? Since the 1980s, it has been argued it would be better to identify Duchenne muscular dystrophy carrier mothers, rather than diagnose their affected sons. Carrier screening for recessive disorders can identify couples with a high chance of having affected children. It allows couples reproductive choice and can prevent infant morbidity and mortality and significant distress for families. Professional bodies in many countries now recommend prospective parents should be informed about carrier screening. Implementing and funding expensive therapies increases the cost-effectiveness of carrier screening, increasing its attractiveness to governments. Best practice for genetic neuromuscular disorders should include equitable access to carrier screening.

Publication

Evidence of Altered Guinea Pig Ventricular Cardiomyocyte Protein Expression and Growth in Response to a 5 min in vitro Exposure to H2O2

Publisher: American Chemical Society (ACS)

Date: 26-02-2010

DOI: 10.1021/PR9011393

Abstract: Oxidative stress and alterations in cellular calcium homeostasis are associated with the development of cardiac hypertrophy. However, the early cellular mechanisms for the development of hypertrophy are not well understood. Guinea pig ventricular myocytes were exposed to 30 microM H(2)O(2) for 5 min followed by 10 units/mL catalase to degrade the H(2)O(2), and effects on protein expression were examined 48 h later. Transient exposure to H(2)O(2) increased the level of protein synthesis more than 2-fold, assessed as incorporation of [(3)H]leucine (n = 12 p < 0.05). Cell size was increased slightly, but there was no evidence of major cytoskeletal disorganization assessed using fluorescence microscopy. Changes in the expression of in idual proteins were assessed using iTRAQ protein labeling followed by mass spectrometry analysis (LC-MALDI-MSMS) 669 proteins were identified, and transient exposure of myocytes to H(2)O(2) altered expression of 35 proteins that were predominantly mitochondrial in origin, including TCA cycle enzymes and oxidative phosphorylation proteins. Consistent with changes in the expression of mitochondrial proteins, transient exposure of myocytes to H(2)O(2) increased the magnitude of the mitochondrial NADH signal 10.5 +/- 2.3% compared to cells exposed to 0 microM H(2)O(2) for 5 min followed by 10 units/mL catalase (n = 8 p < 0.05). In addition, metabolic activity was significantly increased in the myocytes 48 h after transient exposure to H(2)O(2), assessed as formation of formazan from tetrazolium salt. We conclude that a 5 min exposure of ventricular myocytes to 30 microM H(2)O(2) is sufficient to significantly alter protein expression, consistent with the development of hypertrophy in the myocytes. Changes in mitochondrial protein expression and function appear to be early sequelae in the development of hypertrophy.

Publication

Expanded reproductive carrier screening—how can we do the most good and cause the least harm?

Publisher: Springer Science and Business Media LLC

Date: 13-02-2019

DOI: 10.1038/S41431-019-0356-Y

Publication

Dissociated Flexor Digitorum Brevis Myofiber Culture System-A More Mature Muscle Culture System

Publisher: Wiley

Date: 2007

DOI: 10.1002/CM.20223

Abstract: Considerable knowledge regarding skeletal muscle physiology and disease has been gleaned from cultured myoblastic cell lines or isolated primary myoblasts. Such muscle cultures can be induced to differentiate into multinucleated myotubes that become striated. However they in general do not fully mature and therefore do not model mature muscle. Contrastingly, fresh and cultured dissociated adult mouse flexor digitorum brevis (FDB) myofibers have been studied for many years. We aimed to investigate the possibility of using the FDB myofiber culture system for drug screening and thus long-term cultures of enzymatically dissociated FDB myofibers were established in 96-well plates. Ca2+ handling experiments were used to investigate the functional state of the myofibers. Imaging of intracellular Ca2+ during electric field stimulation revealed that calcium handling was maintained throughout the culture period of at least 8 days. Western blot and immunostaining analysis showed that the FDB cultures maintained expression of mature proteins throughout the culture period, including alpha-sarcoglycan, dystrophin, fast myosin heavy chain and skeletal muscle alpha-actin. The high levels of the fetal proteins cardiac alpha-actin and utrophin, seen in cultured C2C12 myotubes, were absent in the FDB cultures. The expression of developmentally mature proteins and the absence of fetal proteins, in addition to the maintenance of normal calcium handling, highlights the FDB culture system as a more mature and perhaps more relevant culture system for the study of adult skeletal muscle function. Moreover, it may be a useful system for screening therapeutic agents for the treatment of skeletal muscle disorders.

Publication

Mutations in CYC1, encoding cytochrome c1 subunit of respiratory chain complex III, cause insulin-responsive hyperglycemia

Publisher: Elsevier BV

Date: 08-2013

DOI: 10.1016/J.AJHG.2013.06.015

Publication

Publisher: Springer Science and Business Media LLC

Date: 12-01-2018

DOI: 10.1038/S41431-017-0013-2

Publication

Early-onset Parkinson disease caused by a mutation in CHCHD2 and mitochondrial dysfunction

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2018

DOI: 10.1212/NXG.0000000000000276

Abstract: Our goal was to identify the gene(s) associated with an early-onset form of Parkinson disease (PD) and the molecular defects associated with this mutation. We combined whole-exome sequencing and functional genomics to identify the genes associated with early-onset PD. We used fluorescence microscopy, cell, and mitochondrial biology measurements to identify the molecular defects resulting from the identified mutation. Here, we report an association of a homozygous variant in CHCHD2 , encoding coiled-coil-helix-coiled-coil-helix domain containing protein 2, a mitochondrial protein of unknown function, with an early-onset form of PD in a 26-year-old Caucasian woman. The CHCHD2 mutation in PD patient fibroblasts causes fragmentation of the mitochondrial reticular morphology and results in reduced oxidative phosphorylation at complex I and complex IV. Although patient cells could maintain a proton motive force, reactive oxygen species production was increased, which correlated with an increased metabolic rate. Our findings implicate CHCHD2 in the pathogenesis of recessive early-onset PD, expanding the repertoire of mitochondrial proteins that play a direct role in this disease.

Publication

Ovine congenital progressive muscular dystrophy (OCPMD) is a model of TNNT1 congenital myopathy

Publisher: Springer Science and Business Media LLC

Date: 20-08-2020

DOI: 10.1186/S40478-020-01017-1

Abstract: Ovine congenital progressive muscular dystrophy (OCPMD) was first described in Merino sheep flocks in Queensland and Western Australia in the 1960s and 1970s. The most prominent feature of the disease is a distinctive gait with stiffness of the hind limbs that can be seen as early as 3 weeks after birth. The disease is progressive. Histopathological examination had revealed dystrophic changes specifically in type I (slow) myofibres, while electron microscopy had demonstrated abundant nemaline bodies. Therefore, it was never certain whether the disease was a dystrophy or a congenital myopathy with dystrophic features. In this study, we performed whole genome sequencing of OCPMD sheep and identified a single base deletion at the splice donor site (+ 1) of intron 13 in the type I myofibre-specific TNNT1 gene (KT218690 c.614 + 1delG). All affected sheep were homozygous for this variant. Examination of TNNT1 splicing by RT-PCR showed intron retention and premature termination, which disrupts the highly conserved 14 amino acid C-terminus. The variant did not reduce TNNT1 protein levels or affect its localization but impaired its ability to modulate muscle contraction in response to Ca 2+ levels. Identification of the causative variant in TNNT1 finally clarifies that the OCPMD sheep is in fact a large animal model of TNNT1 congenital myopathy. This model could now be used for testing molecular or gene therapies.

Publication

Three novel mutations and two variants in the gene for Cu/Zn superoxide dismutase in familial amyotrophic lateral sclerosis

Publisher: Elsevier BV

Date: 10-1996

DOI: 10.1016/0960-8966(96)00353-7

Abstract: Autosomal dominant inheritance is exhibited by about 10% of cases of amyotrophic lateral sclerosis (ALS), a paralytic disorder characterized by the death of motor neurons in the brain and spinal cord. A subgroup of these familial cases are linked to mutations in the gene which codes for Cu/Zn superoxide dismutase (SOD1). We report three additional mutations occurring in the SOD1 gene in ALS patients and two single base pair variant changes. The single base pair change in an ALS family causes a glycine 93 to valine substitution, which is the fifth distinct amino acid change reported for the glycine 93 residue. One missense mutation in exon 5 would substitute neutral valine for the negatively-charged aspartate 124 (aspartate 124 to valine). An in idual with an apparently sporadic case of ALS carries a three base pair deletion in exon 5 of the SOD1 gene. These three mutations bring to 38 the total number of distinct SOD1 mutations associated with familial ALS.

Publication

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 11-04-2020

DOI: 10.1212/01.WNL.0000156524.95261.B9

Publication

Intranuclear nemaline rod myopathy

Publisher: Wiley

Publisher: Elsevier BV

Date: 12-2013

DOI: 10.1016/J.AJHG.2013.10.020

Publication

Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant

Publisher: Hindawi Limited

Date: 13-01-2018

DOI: 10.1002/HUMU.23385

Publication

Whole exome sequencing in foetal akinesia expands the genotype–phenotype spectrum of GBE1 glycogen storage disease mutations

Publisher: Elsevier BV

Date: 02-2013

DOI: 10.1016/J.NMD.2012.11.005

Abstract: The clinically and genetically heterogenous foetal akinesias have low rates of genetic diagnosis. Exome sequencing of two siblings with phenotypic lethal multiple pterygium syndrome identified compound heterozygozity for a known splice site mutation (c.691+2T>C) and a novel missense mutation (c.956A>G p.His319Arg) in glycogen branching enzyme 1 (GBE1). GBE1 mutations cause glycogen storage disease IV (GSD IV), including a severe foetal akinesia sub-phenotype. Re-investigating the muscle pathology identified storage material, consistent with GSD IV, which was confirmed biochemically. This study highlights the power of exome sequencing in genetically heterogeneous diseases and adds multiple pterygium syndrome to the phenotypic spectrum of GBE1 mutation.

Publication

Publisher: Elsevier BV

Date: 03-2023

DOI: 10.1016/J.AJHG.2023.01.018

Publication

Assignment of the human α-tropomyosin gene TPM4 to band 19p13.1 by fluorescence in situ hybridization

Publisher: S. Karger AG

Date: 1996

DOI: 10.1159/000134206

Abstract: Sequence-tagged sites (STSs) were developed for the human α-tropomyosin gene TPM4. One STS was used to lify DNA from somatic cell hybrids to localize TPM4 to chromosome 19. The other, a product from a long-range PCR, was used directly as a probe to refine the localization of TPM4 to 19p13.1 by fluorescence in situ hybridization to metaphase chromosome spreads.

Publication

Actin nemaline myopathy mouse reproduces disease, suggests other Actin Disease phenotypes and provides cautionary note on muscle transgene expression

Publisher: Public Library of Science (PLoS)

Date: 09-12-2011

DOI: 10.1371/JOURNAL.PONE.0028699

Publication

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2007

DOI: 10.1097/WCO.0B013E3282EF6E69

Publication

The Australian Reproductive Genetic Carrier Screening Project (Mackenzie’s Mission)

Publisher: MDPI AG

Date: 28-10-2022

DOI: 10.3390/JPM12111781

Abstract: Reproductive genetic carrier screening (RGCS) provides people with information about their chance of having children with autosomal recessive or X-linked genetic conditions, enabling informed reproductive decision-making. RGCS is recommended to be offered to all couples during preconception or in early pregnancy. However, cost and a lack of awareness may prevent access. To address this, the Australian Government funded Mackenzie’s Mission—the Australian Reproductive Genetic Carrier Screening Project. Mackenzie’s Mission aims to assess the acceptability and feasibility of an easily accessible RGCS program, provided free of charge to the participant. In study Phase 1, implementation needs were mapped, and key study elements were developed. In Phase 2, RGCS is being offered by healthcare providers educated by the study team. Reproductive couples who provide consent are screened for over 1200 genes associated with serious, childhood-onset genetic conditions. Those with an increased chance result are provided comprehensive genetic counseling support. Reproductive couples, recruiting healthcare providers, and study team members are also invited to complete surveys and/or interviews. In Phase 3, a mixed-methods analysis will be undertaken to assess the program outcomes, psychosocial implications and implementation considerations alongside an ongoing bioethical analysis and a health economic evaluation. Findings will inform the implementation of an ethically robust RGCS program.

Publication

A second pedigree with autosomal dominant nemaline myopathy caused by TPM3 mutation: A clinical and pathological study

Publisher: Elsevier BV

Date: 04-2007

DOI: 10.1016/J.NMD.2007.01.017

Abstract: The slow alpha-tropomyosin (TPM3) gene has to date been associated with few cases of both dominant and recessive nemaline myopathies. We report the identification of a p.Arg167His mutation in a four-generation family presenting with a mild classical form of the disease. Clinically, there was no correlation between the age at presentation and the severity of the disease. The dominant-negative p.Arg167His mutation is a recurrent mutation, previously reported in one sporadic case. Histological studies showed discrepancy between the two reports. While a type II fibre predominance was described in the sporadic case, we observed an almost complete type I fibre predominance. This study emphasizes the variability in histopathological phenotypes seen with TPM3 mutations.

Publication

A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families

Publisher: Oxford University Press (OUP)

Date: 10-2020

DOI: 10.1093/BRAIN/AWAA263

Abstract: Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected in iduals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in in iduals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from & 000 genetically erse in iduals in gnomAD to show enrichment of (ACAGG) in non-European populations.

Publication

Autosomal dominant distal myopathy not linked to the known distal myopathy loci

Publisher: Elsevier BV

Date: 03-1999

DOI: 10.1016/S0960-8966(98)00099-6

Abstract: The distal myopathies are clinically, pathologically and genetically heterogenous. Thus far, seven types of distal myopathy have been linked to four chromosome loci. We recently examined four affected members from three generations of an autosomal dominant distal myopathy kindred. A muscle biopsy was performed on the index case. Muscle histopathology showed non-specific myopathic findings including increased variation in fiber size and increased internalized nuclei. No abnormal inclusions or vacuoles were present. Microsatellite markers for the four distal myopathy loci on chromosomes 2, 9 and 14 were studied on affected and several unaffected family members. Affected patients developed distal weakness in anterior foreleg muscles followed by progressive distal upper and proximal lower extremity involvement. Chromosome 2, 9 and 14 regional markers were informative and demonstrated recombinations with affected in iduals in the pedigree. The resulting LOD scores obtained from the multipoint analyses gave no evidence of positive linkage to any of the regions and positively excluded (LOD score less than -2) all, or virtually all, of the candidate regions examined. This autosomal dominant distal myopathy family does not show evidence of linkage to any of the known distal myopathy loci, suggesting the existence of at least one more distal myopathy locus. Furthermore, the clinical and pathological features appear distinct from other previously described but genetically-undetermined autosomal dominant distal myopathies.

Publication

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1016/J.NMD.2013.02.009

Publication

Study protocol of a multicentre cohort pilot study implementing an expanded preconception carrier-screening programme in metropolitan and regional Western Australia

Publisher: BMJ

Publisher: Springer Science and Business Media LLC

Date: 30-09-2020

DOI: 10.1007/S40291-020-00495-2

Publication

Investigation of changes in skeletal muscle α-actin expression in normal and pathological human and mouse hearts

Publisher: Springer Science and Business Media LLC

Date: 13-08-2010

DOI: 10.1007/S10974-010-9224-7

Abstract: We have developed a quantitative antibody-based assay to measure the content of skeletal muscle alpha-actin relative to cardiac alpha-actin. We found 21 +/- 2% skeletal muscle alpha-actin content in normal heart muscle of adult man and mouse. In end stage failing heart 53 +/- 5% of striated actin was skeletal muscle alpha-actin and in s les of inter-ventricular septum from patients with hypertrophic obstructive cardiomyopathy (HOCM) skeletal muscle alpha-actin was 72 +/- 2% of sarcomeric actin. Thin filaments containing actin isolated from normal and HOCM heart muscle were functionally indistinguishable when studied by quantitative in vitro motility assay. We also found elevated skeletal muscle alpha-actin (60 +/- 7%) in a mouse model of dilated cardiomyopathy.

Publication

Publisher: Elsevier BV

Date: 04-2009

DOI: 10.1016/J.NMD.2009.02.002

Publication

K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity

Publisher: Oxford University Press (OUP)

Publisher: Frontiers Media SA

Date: 20-05-2028

DOI: 10.3389/FPUBH.2017.00025

Publication

Effectiveness of posthumous molecular diagnosis from a kept baby tooth

Publisher: Elsevier BV

Date: 10-2005

DOI: 10.1016/S0140-6736(05)67631-3

Publication

Biallelic variants inHMGCS1are a novel cause of rare rigid spine syndrome

Publisher: Cold Spring Harbor Laboratory

Date: 28-10-2023

DOI: 10.1101/2023.10.25.23297129

Publication

Publisher: Elsevier BV

Date: 2006

DOI: 10.1016/J.NMD.2005.10.006

Publication

CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: Expanding the phenotypic spectrum of caveolinopathies

Publisher: Elsevier BV

Date: 08-2016

DOI: 10.1016/J.NMD.2016.05.006

Abstract: Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7), exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other "typical" features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes.

Publication

Publisher: Elsevier BV

Date: 10-2014

DOI: 10.1016/J.NMD.2014.06.065

Publication

Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin

Publisher: Springer Science and Business Media LLC

Date: 02-04-2008

DOI: 10.1038/EJHG.2008.60

Abstract: To date, six genes are known to cause nemaline (rod) myopathy (NM), a rare congenital neuromuscular disorder. In an attempt to find a seventh gene, we performed linkage and subsequent sequence analyses in 12 Turkish families with recessive NM. We found homozygosity in two of the families at 1q12-21.2, a region encompassing the gamma-tropomyosin gene (TPM3) encoding slow skeletal muscle alpha-tropomyosin, a known NM gene. Sequencing revealed homozygous deletion of the first nucleotide of the last exon, c.913delA of TPM3 in both families. The mutation removes the last nucleotide before the stop codon, causing a frameshift and readthrough across the termination signal. The encoded alphaTm(slow) protein is predicted to be 73 amino acids longer than normal, and the extension to the protein is hypothesised to be unable to form a coiled coil. The resulting tropomyosin protein may therefore be non-functional. The affected children in both families were homozygous for the mutation, while the healthy parents were mutation carriers. Both of the patients in Family 1 had the severe form of NM, and also an unusual chest deformity. The affected children in Family 2 had the intermediate form of NM. Muscle biopsies showed type 1 (slow) fibres to be markedly smaller than type 2 (fast) fibres. Previously, there had been five reports, only, of NM caused by mutations in TPM3. The mutation reported here is the first deletion to be identified in TPM3, and it is likely to be a founder mutation in the Turkish population.

Publication

Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations

Publisher: Elsevier BV

Date: 12-2004

DOI: 10.1016/J.NMD.2004.08.006

Abstract: Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are associated with a wide range of phenotypes, comprising central core disease and distinct subgroups of multi-minicore disease. We report muscle MRI findings of 11 patients from eight families with RYR1 mutations (n=9) or confirmed linkage to the RYR1 locus (n=2). Patients had clinical features of a congenital myopathy with a wide variety of associated histopathological changes. Muscle MR images showed a consistent pattern characterized by (a) within the thigh: selective involvement of vasti, sartorius, adductor magnus and relative sparing of rectus, gracilis and adductor longus (b) within the lower leg: selective involvement of soleus, gastrocnemii and peroneal group and relative sparing of the tibialis anterior. Our findings indicate that patients with RYR1-related congenital myopathies have a recognizable pattern of muscle involvement irrespective of the variability of associated histopathological findings. Muscle MRI may supplement clinical assessment and aid selection of genetic tests particularly in patients with non-diagnostic or equivocal histopathological features.

Publication

Nemaline myopathy type 6: Clinical and myopathological features

Publisher: Wiley

Date: 22-11-2010

DOI: 10.1002/MUS.21788

Publication

Consensus Statement on Standard of Care for Congenital Myopathies

Publisher: SAGE Publications

Date: 03-2012

DOI: 10.1177/0883073812436605

Abstract: Recent progress in scientific research has facilitated accurate genetic and neuropathological diagnosis of congenital myopathies. However, given their relatively low incidence, congenital myopathies remain unfamiliar to the majority of care providers, and the levels of patient care are extremely variable. This consensus statement aims to provide care guidelines for congenital myopathies. The International Standard of Care Committee for Congenital Myopathies worked through frequent e-mail correspondences, periodic conference calls, 2 rounds of online surveys, and a 3-day workshop to achieve a consensus for diagnostic and clinical care recommendations. The committee includes 59 members from 10 medical disciplines. They are organized into 5 working groups: genetics/diagnosis, neurology, pulmonology, gastroenterology/nutrition/speech/oral care, and orthopedics/rehabilitation. In each care area the authors summarize the committee’s recommendations for symptom assessments and therapeutic interventions. It is the committee’s goal that through these recommendations, patients with congenital myopathies will receive optimal care and improve their disease outcome.

Publication

Publisher: Elsevier BV

Date: 02-2014

DOI: 10.1016/J.NMD.2013.11.003

Publication

‘Cap myopathy’: Case report of a family

Publisher: Elsevier BV

Date: 04-2006

DOI: 10.1016/J.NMD.2006.01.014

Abstract: We report the observation of an 18-year-old girl, whose clinical presentation was very suggestive of a congenital myopathy with neonatal onset. A congenital myopathy had been already diagnosed in her brother and in addition her half-cousin died diagnosed with a severe nemaline myopathy at age 4 years. A muscle biopsy performed on both siblings revealed histological and ultrastructural features of 'cap myopathy'. This case report suggests that 'cap myopathy' and some cases of nemaline myopathy with neonatal onset might be two phenotypic expressions of the same genetic disorder. These two entities could therefore, perhaps, be regarded as 'Z-line disorders' possibly caused by defective myofibrillogenesis.

Publication

Distal myosin heavy chain-7 myopathy due to the novel transition c.5566G>A (p.E1856K) with high interfamilial cardiac variability and putative anticipation

Publisher: Elsevier BV

Date: 08-2014

DOI: 10.1016/J.NMD.2014.05.010

Abstract: Myosin-heavy-chain 7 (MYH7)-myopathy manifests clinically with a distal, scapuloperoneal, limb-girdle (proximal), or axial distribution and may involve the respiratory muscles. Cardiac involvement is frequent, ranging from relaxation impairment to severe dilative cardiomyopathy. Progression and earlier onset of cardiac disease in successive generations with MYH7-myopathy is unreported. In a five-generation family MYH7-myopathy due to the novel c.5566G > A (p.E1856K) mutation manifested with late-onset, distal > proximal myopathy and variable degree of cardiac involvement. The index patient developed distal myopathy since age 49 y and anginal chest pain. Her mother had distal myopathy and impaired myocardial relaxation. The daughter of the index patient had discrete myopathy but left ventricular hypertrabeculation/noncompaction and ventricular arrhythmias requiring an implantable cardioverter defibrillator. The granddaughter of the index patient had infantile dilated cardiomyopathy without overt myopathy. Cardiac involvement may be present in MYH7-myopathy and may be progressive between the generations, ranging from relaxation abnormality to noncompaction, ventricular arrhythmias, and dilated cardiomyopathy.

Publication

Publisher: Springer Science and Business Media LLC

Date: 27-04-2022

DOI: 10.1038/S41431-021-00885-Y

Publication

Dystrophin gene transcripts skipping the mdx mutation

Publisher: Wiley

Date: 06-1997

DOI: 10.1002/(SICI)1097-4598(199706)20:6<728::AID-MUS10>3.0.CO;2-Q

Abstract: The mdx mouse, an animal model used to study Duchenne muscular dystrophy, has a nonsense mutation in exon 23 of the dystrophin gene which should result in a truncated protein that cannot be correctly localized at the sarcolemma of the muscle fibers. Immunohistochemical staining with antidystrophin antibodies has shown that while most of the muscle tissue is dystrophin-negative, a small percentage of muscle fibers is clearly dystrophin-positive and has somehow bypassed the primary nonsense mutation. A sensitive nested polymerase chain reaction-based examination of dystrophin gene transcripts around the mdx mutation has revealed several alternatively processed transcripts. Four mRNA species skipped the mutation in exon 23, were in-frame, and could be translated into a shorter but still functional dystrophin protein. Specific tests for these transcripts demonstrated these were also present in normal mouse muscle tissue.

Publication

Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function

Publisher: Springer Science and Business Media LLC

Date: 05-2015

DOI: 10.1007/S00401-015-1430-3

Publication

Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization

Publisher: Elsevier BV

Date: 11-2016

DOI: 10.1016/J.AJHG.2016.09.005

Publication

A Genotype-First Approach for the Molecular and Clinical Characterization of Uncommon De Novo Microdeletion of 20q13.33

Publisher: Public Library of Science (PLoS)

Date: 27-08-2010

DOI: 10.1371/JOURNAL.PONE.0012462

Publication

Variants in ACTG2 underlie a substantial number of Australasian patients with primary chronic intestinal pseudo‐obstruction

Publisher: Wiley

Date: 21-05-2018

DOI: 10.1111/NMO.13371

Abstract: Primary chronic intestinal pseudo-obstruction (CIPO) is a rare, potentially life-threatening disorder characterized by severely impaired gastrointestinal motility. The objective of this study was to examine the contribution of ACTG2, LMOD1, MYH11, and MYLK mutations in an Australasian cohort of patients with a diagnosis of primary CIPO associated with visceral myopathy. Pediatric and adult patients with primary CIPO and suspected visceral myopathy were recruited from across Australia and New Zealand. Sanger sequencing of the genes encoding enteric gamma-actin (ACTG2) and smooth muscle leiomodin (LMOD1) was performed on DNA from patients, and their relatives, where available. MYH11 and MYLK were screened by next-generation sequencing. We identified heterozygous missense variants in ACTG2 in 7 of 17 families (~41%) diagnosed with CIPO and its associated conditions. We also identified a previously unpublished missense mutation (c.443C>T, p.Arg148Leu) in one family. One case presented with megacystis-microcolon-intestinal hypoperistalsis syndrome in utero with subsequent termination of pregnancy at 28 weeks' gestation. All of the substitutions identified occurred at arginine residues. No likely pathogenic variants in LMOD1, MYH11, or MYLK were identified within our cohort. ACTG2 mutations represent a significant underlying cause of primary CIPO with visceral myopathy and associated phenotypes in Australasian patients. Thus, ACTG2 sequencing should be considered in cases presenting with hypoperistalsis phenotypes with suspected visceral myopathy. It is likely that variants in other genes encoding enteric smooth muscle contractile proteins will contribute further to the genetic heterogeneity of hypoperistalsis phenotypes.

Publication

Publisher: Wiley

Date: 30-09-2002

DOI: 10.1046/J.1365-2052.2002.00896_7.X

Publication

Publisher: Oxford University Press (OUP)

Date: 15-06-2004

DOI: 10.1093/HMG/DDH185

Publication

Laing early onset distal myopathy: slow myosin defect with variable abnormalities on muscle biopsy

Publisher: BMJ

Date: 02-2006

DOI: 10.1136/JNNP.2005.073825

Publication

Bi-allelic mutations in MYL1 cause a severe congenital myopathy

Publisher: Oxford University Press (OUP)

Date: 12-09-2018

DOI: 10.1093/HMG/DDY320

Publication

Mutations in nucleoporinNUP88cause lethal neuromuscular disorder

Publisher: Cold Spring Harbor Laboratory

Date: 14-06-2018

DOI: 10.1101/347179

Abstract: Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, are of outmost importance for normal cell function. Defects in the process of nucleocytoplasmic transport or in its machinery have been frequently described in human diseases, such as cancer and neurodegenerative disorders, but only in a few cases of developmental disorders. Here we report biallelic mutations in the nucleoporin NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS) in two families. FADS comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Phenotypic alterations become visible at distinct developmental stages, both in affected human fetuses and in zebrafish, whereas early stages of development are apparently normal. The zebrafish phenotypes caused by nup88 deficiency are only rescued by expressing wild-type nup88 and not the disease-linked mutant forms of nup88. Furthermore, using human and mouse cell lines as well as immunohistochemistry on fetal muscle tissue, we demonstrate that NUP88 depletion affects rapsyn, a key regulator of the muscle nicotinic acetylcholine receptor at the neuromuscular junction. Together, our studies provide the first characterization of NUP88 in vertebrate development, expand our understanding of the molecular events causing FADS, and suggest that variants in NUP88 should be investigated in cases of FADS.

Publication

Publisher: Elsevier BV

Date: 10-2015

DOI: 10.1016/J.NMD.2015.06.404

Publication

Lethal multiple pterygium syndrome

Publisher: Elsevier BV

Date: 06-2017

DOI: 10.1016/J.NMD.2017.01.013

Abstract: Fetal akinesia deformation sequence is a clinically and genetically heterogeneous disorder characterized by a variable combination of fetal akinesia, intrauterine growth restriction, developmental abnormalities such as cystic hygroma, hydrops fetalis, pulmonary hypoplasia, occasional arthrogryposis, and pterygia. The pathogenetic mechanisms of fetal akinesia deformation sequence include neuropathy, muscular disorders, neuromuscular junction disorders, maternal myasthenia gravis, restrictive dermopathy and others. We here report an Egyptian family presenting with recurrent lethal multiple pterygium syndrome. The diagnosis was based on antenatal sonographic demonstration of complete fetal akinesia and a large cystic hygroma with severe limb contractures evident on postmortem examination. Next generation sequencing performed on the second affected fetus identified a novel homozygous essential splice-site variant in the nebulin gene. In conclusion, our report adds further evidence for the involvement of the nebulin gene in the etiology of fetal akinesia deformation sequence/lethal multiple pterygium syndrome.

Publication

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing

Publisher: Cold Spring Harbor Laboratory

Date: 10-2021

DOI: 10.1101/2021.09.27.21263187

Abstract: Short-tandem repeat (STR) expansions are an important class of pathogenic genetic variants. Over forty neurological and neuromuscular diseases are caused by STR expansions, with 37 different genes implicated to date. Here we describe the use of programmable targeted long-read sequencing with Oxford Nanopore’s ReadUntil function for parallel genotyping of all known neuropathogenic STRs in a single, simple assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of expanded and non-expanded STR sites. In doing so, the assay correctly diagnoses all in iduals in a cohort of patients ( n = 27) with various neurogenetic diseases, including Huntington’s disease, fragile X syndrome and cerebellar ataxia (CANVAS) and others. Targeted long-read sequencing solves large and complex STR expansions that confound established molecular tests and short-read sequencing, and identifies non-canonical STR motif conformations and internal sequence interruptions. Even in our relatively small cohort, we observe a wide ersity of STR alleles of known and unknown pathogenicity, suggesting that long-read sequencing will redefine the genetic landscape of STR expansion disorders. Finally, we show how the flexible inclusion of pharmacogenomics (PGx) genes as secondary ReadUntil targets can identify clinically actionable PGx genotypes to further inform patient care, at no extra cost. Our study addresses the need for improved techniques for genetic diagnosis of STR expansion disorders and illustrates the broad utility of programmable long-read sequencing for clinical genomics. This study describes the development and validation of a programmable targeted nanopore sequencing assay for parallel genetic diagnosis of all known pathogenic short-tandem repeats (STRs) in a single, simple test.

Publication

Measuring the impact of genetic knowledge on intentions and attitudes of the community towards expanded preconception carrier screening

Publisher: BMJ

Date: 08-2018

DOI: 10.1136/JMEDGENET-2018-105362

Abstract: Preconception carrier screening (PCS) provides the potential to empower couples to make reproductive choices before having an affected child. An important question is what factors influence the decision to use or not use PCS. We analysed the relationship between knowledge, attitudes and intentions to participate in PCS using logistic regression in 832 participants in Western Australia. Two-thirds of participants said they would take the test, with 92% of these supporting screening for diseases reducing the lifespan of children and infants. Those who had good genetic knowledge were seven times more likely to intend to use PCS (p≤0.001), while those with high genetic knowledge were four times more likely to (p=0.002) and raised concerns such as insurance and confidentiality. Decreasing genetic knowledge correlated positively with religiosity and apprehension (p≤0.001), which correlated negatively with intention to use PCS (p≤0.001). Increasing genetic knowledge correlated positively with factors representing positive attitudes (p≤0.001), which correlated positively with intention to use PCS (p≤0.001). Many participants with good genetic knowledge nevertheless answered questions that tested understanding incorrectly. 80% of participants stated they would prefer to access the test through their general practitioners and 30% would pay up to $A200. Knowledge is instrumental in influencing participation. Having good genetic knowledge may not be enough to understand core concepts of PCS and may impact informed decision-making. This study recommends that continuous education of health professionals and thus the community, in PCS is crucial to reduce misconceptions.

Publication

Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebuline and skeletal muscle α-actin

Publisher: Elsevier BV

Date: 09-2004

DOI: 10.1016/J.NMD.2004.03.006

Publication

Nemaline Rods and Complex I Deficiency in Three Infants with Hypotonia, Motor Delay and Failure to Thrive

Publisher: Georg Thieme Verlag KG

Date: 10-2004

DOI: 10.1055/S-2004-821243

Abstract: Three infants are described who had nemaline rods on muscle biopsy and isolated deficiency of complex I of the respiratory chain on biochemical analysis. They all manifested failure to thrive from birth, and hypotonia and muscle weakness within the first three months of life. Different genetic defects leading to isolated complex I deficiency have been described associated with a variety of morphological changes on muscle biopsy, but rods have not been described. Nemaline rods have been secondary phenomena in a number of conditions, as well as being the primary abnormality in nemaline myopathy. However, the combination of nemaline rods and complex I deficiency is an association not previously reported.

Publication

Utility of a next-generation sequencing (NGS)-based neuromuscular disease gene panel in an investigation of 30 families with early-onset presentation from a tertiary pediatric neuromuscular clinic

Publisher: Elsevier BV

Date: 10-2017

DOI: 10.1016/J.NMD.2017.06.371

Publication

Publisher: Elsevier BV

Date: 02-2210

DOI: 10.1016/J.AJHG.2007.10.001

Publication

Severe nemaline myopathy caused by mutations of the stop codon of the skeletal muscle alpha actin gene (ACTA1)

Publisher: Elsevier BV

Date: 10-2006

DOI: 10.1016/J.NMD.2006.07.018

Abstract: Most nemaline myopathy patients have mutations in the nebulin (NEB) or skeletal muscle alpha-actin (ACTA1) genes. Here we report for the first time three patients with severe nemaline myopathy and mutations of the ACTA1 stop codon: TAG>TAT (tyrosine), TAG>CAG (glutamine) and TAG>TGG (tryptophan). All three mutations will cause inclusion of an additional 47 amino acids, translated from the 3' UTR of the gene, into the mature actin protein. Western blotting of one patient's muscle demonstrated the presence of the larger protein, while expression of one of the other mutant proteins fused to EGFP in C2C12 cells demonstrated the formation of rod bodies.

Publication

Genetic Counselling Needs for Reproductive Genetic Carrier Screening: A Scoping Review

Publisher: MDPI AG

Date: 11-10-2022

DOI: 10.3390/JPM12101699

Abstract: Reproductive genetic carrier screening provides in iduals and couples with information regarding their risk of having a child affected by an autosomal recessive or X-linked recessive genetic condition. This information allows them the opportunity to make reproductive decisions in line with their own beliefs and values. Traditionally, carrier screening has been accessed by family members of affected in iduals. In recent years, improvements to accessibility and updates to recommendations suggest that all women planning or in early pregnancy should be offered reproductive genetic carrier screening. As uptake moves towards the population scale, how can the genetic counselling needs of such large-scale screening be met? A scoping review of the literature was performed to ascertain what the genetic counselling needs of reproductive genetic carrier screening are, and what future research is needed. Four broad themes were identified in the existing literature: (1) The offer—when and in what context to offer screening (2) Information—the importance of and what to include in education, and pre- and post-test counselling (3) Who and how—who the genetic counselling is performed by and how (4) Personalization—how do we find the balance between standardized and in idualized approaches? Based on the existing literature, we present a set of recommendations for consideration in implementing population-scale reproductive genetic carrier screening as well as suggested areas for future research.

Publication

Publisher: Elsevier BV

Date: 10-2014

DOI: 10.1016/J.NMD.2014.06.023

Publication

Myopathies resulting from mutations in sarcomeric proteins

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2004

DOI: 10.1097/00019052-200410000-00003

Abstract: The past decade has seen the discovery of the major role that mutations in the protein components of the sarcomere plays as a cause of human muscle disease. An overview of the more precise molecular definitions of these diseases is timely. Recent findings include: the beginnings of an understanding of the role of the sarcomere in controlling muscle gene expression the theoretical analysis of the increasing number of mutations identified in the skeletal muscle actin gene the identification of mutations in myosin causing hereditary inclusion body myopathy and hyaline body myopathy and the identification of mutations in myotilin in myofibrillar myopathy. An increasing spectrum of human muscle diseases is being shown to be caused by mutations in proteins of all the major components of the sarcomere. Molecular analysis is providing a more accurate delineation of these diseases, but for the giant nebulin and titin genes, molecular diagnosis remains difficult. Treatment options for these disorders will only come through a deeper understanding of the sarcomere and of the pathogenesis of its disorders.

Publication

Publisher: Elsevier BV

Date: 10-2019

DOI: 10.1016/J.NMD.2019.06.390

Publication

NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

Publisher: Springer Science and Business Media LLC

Date: 15-09-2020

DOI: 10.1038/S41467-020-18327-6

Abstract: A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway—Ribosome-associated Quality Control (RQC)—by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF’s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

Publication

Characterization of human muscle type cofilin (CFL2) in normal and regenerating muscle

Publisher: Wiley

Date: 06-2001

DOI: 10.1046/J.1432-1327.2001.02247.X

Abstract: Cofilins are actin binding proteins and regulate actin assembly in vivo. Numerous cofilin homologues have been characterized in various organisms including mammals. In mice, a ubiquitously expressed cofilin (CFL1) and a skeletal muscle specific cofilin (CFL2) have been described. In the present study, we identified and characterized a human CFL2 gene localized on chromosome 14, with high homology to murine CFL2. Furthermore, we provide evidence for differentially spliced CFL2 transcripts (CFL2a and CFL2b). CFL2b is expressed predominantly in human skeletal muscle and heart, while CFL2a is expressed in various tissues. Genetic defects of CFL2 were excluded for one human muscle disorder, the chromosome 14 linked distal myopathy MPD1, and shown to be only possible to be a rare cause of another, nemaline myopathy. In a mouse model of mechanically induced muscle damage the changes of cofilin expression were monitored during the first 10 days of regeneration, with dephosphorylated CFL2 being the major isoform at later stages of muscle regeneration. A similar predominance of dephosphorylated CFL2 was observed in chronically regenerating dystrophin-deficient muscles of Duchenne muscular dystrophy patients. Therefore, the CFL2 isoform may play an important role in normal muscle function and muscle regeneration.

Publication

When contractile proteins go bad: the sarcomere and skeletal muscle disease

Publisher: Wiley

Date: 2005

DOI: 10.1002/BIES.20269

Abstract: The sarcomere is the functional unit of striated muscle contraction. Mutations in sarcomeric proteins are now known to cause around 20 different skeletal muscle diseases. The diseases vary in severity from paralysis at birth, to mild conditions compatible with normal life span. The identification of the disease genes allows more accurate diagnosis, including prenatal diagnosis. Although many disease genes have been identified, the pathophysiology of the gene defects remains remarkably obscure, considering that many of the proteins have been researched for decades. The short-term goals are to determine the remaining disease genes and to decipher pathogenesis. The long-term goal is to develop effective therapies-a daunting task when humans are up to 40% muscle and the mutated proteins are fundamental to muscle contraction. The affected patients and families hope for help sooner rather than later. The onus is on all scientists researching sarcomeric proteins to help develop treatments.

Publication

A CCG expansion inABCD3causes oculopharyngodistal myopathy in individuals of European ancestry

Publisher: Cold Spring Harbor Laboratory

Date: 10-10-2023

DOI: 10.1101/2023.10.09.23296582

Publication

Publisher: Oxford University Press (OUP)

Date: 23-04-2007

DOI: 10.1093/BRAIN/AWM073

Publication

Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor

Publisher: Oxford University Press (OUP)

Date: 12-1998

DOI: 10.1093/HMG/7.13.2045

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegeneration resulting in paralysis and death from respiratory failure within 3-5 years. About 20% of familial cases are associated with mutations in the gene for copper/zinc superoxide dismutase ( SOD1 ), which catalyses the dismutation of the superoxide radical to hydrogen peroxide and oxygen. Experimental evidence suggests mutations act by a toxic gain of function but the mechanism is unknown. There are >60 known SOD1 mutations associated with ALS and all are dominant except for one in exon 4, a D90A substitution which is recessive. D90A pedigrees with dominant inheritance have now been reported and this apparent contradiction needs to be explained. We performed a worldwide haplotype study on 28 D90A pedigrees using six highly polymorphic microsatellite markers. We now show that all 20 recessive families share the same founder (alpha = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (alpha = 0.385). This finding confirms that D90A can act in a dominant fashion in keeping with all other SOD1 mutations, but that on one occasion, a new instance of this mutation has been recessive. We propose a tightly linked protective factor which modifies the toxic effect of mutant SOD1 in recessive families.

Nigel Laing

Researcher

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Publications

Clinical utility gene card for: Laing distal myopathy

Congenital Nemaline Myopathy due to ACTA1-Gene Mutation and Carnitine Insufficiency: A Case Report

Identification of a point mutation and germinal mosaicism in a duchenne muscular dystrophy family

Variable cardiac α-actin (Actc1) expression in early adult skeletal muscle correlates with promoter methylation

BIN1 founder mutation in the Spanish gypsy population is the most frequent cause of adult onset centronuclear myopathies in the south of Spain

Sporadic inclusion body myositis in Japanese is associated with the MHC ancestral haplotype 52.1

TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype

Clinical utility gene card for: Nemaline myopathy

Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene

Pathophysiological concepts in the congenital myopathies: blurring the boundaries, sharpening the focus

Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions

A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy

The spectrum of pathology in central core disease

Assignment of the human skeletal muscle a-tropomyosin gene (TPM1) to band 15q22 by fluorescence in situ hybridization

Nemaline myopathy with stiffness and hypertonia associated with an ACTA1 mutation

Myosin storage (hyaline body) myopathy: A case report

Actin myopathy with nemaline bodies, intranuclear rods, and a heterozygous mutation in ACTA1 (Asp154Asn)

Allelic loss of cyclophilin 40, an estrogen receptor-associated immunophilin, in breast carcinomas

Distal arthrogryposis type 5D with novel clinical features and compound heterozygous mutations in ECEL1

Diagnosis of fetal akinesia and arthrogryposis by panel sequencing and functional genomics

Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies

Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2

Correspondence on “Screening for autosomal recessive and X-linked conditions during pregnancy and preconception

Nemaline myopathy caused by absence of α-skeletal muscle actin

Nemaline Myopathy with Minicores Caused by Mutation of the CFL2 Gene Encoding the Skeletal Muscle Actin–Binding Protein, Cofilin-2

Clinical Utility Gene Card for autosomal dominant myotonia congenita (Thomsen Disease)

STRetch: detecting and discovering pathogenic short tandem repeat expansions

A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy

Nemaline Myopathy: A Clinical study of 143 cases

Partial loss‐of‐function variant in neuregulin 1 identified in family with heritable peripheral neuropathy

Genetic neuromuscular disorders: what is the best that we can do?

Evidence of Altered Guinea Pig Ventricular Cardiomyocyte Protein Expression and Growth in Response to a 5 min in vitro Exposure to H2O2

Expanded reproductive carrier screening—how can we do the most good and cause the least harm?

Dissociated Flexor Digitorum Brevis Myofiber Culture System-A More Mature Muscle Culture System

Mutations in CYC1, encoding cytochrome c1 subunit of respiratory chain complex III, cause insulin-responsive hyperglycemia

Genetic and histological characterisation of excitation-contraction coupling related structural myopathy cohort

Cardiac -actin over-expression therapy in dominant ACTA1 disease

The relationship between beta-ureidopropionase deficiency due to UPB1 variants and human phenotypes is uncertain

Myopathy mutations in α-skeletal-muscle actin cause a range of molecular defects

Mutations in the Slow Skeletal Muscle Fiber Myosin Heavy Chain Gene (MYH7) Cause Laing Early-Onset Distal Myopathy (MPD1)

Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure

STRling: a k-mer counting approach that detects short tandem repeat expansions at known and novel loci

Generation of two isogenic induced pluripotent stem cell lines from a 1-month-old nemaline myopathy patient harbouring a homozygous recessive c.121C > T (p.Arg39Ter) variant in the ACTA1 gene

Central core disease: clinical, pathological, and genetic features

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing

Loss-of-function mutations inSCN4Acause severe foetal hypokinesia or ‘classical’ congenital myopathy

Characterisation of the chicken Cu, Zn superoxide dismutase gene

Ataxia-telangiectasia-like disorder in a family deficient for MRE11A, caused by a MRE11 variant

Cystinosis distal myopathy, novel clinical, pathological and genetic features

Recent advances in understanding congenital myopathies

Adult onset distal and proximal myopathy with complete ophthalmoplegia associated with a novel de novo p.(Leu1877Pro) mutation in MYH2

Novel Application of Flow Cytometry: Determination of Muscle Fiber Types and Protein Levels in Whole Murine Skeletal Muscles and Heart

Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia

Identification of a novel heterozygous DYSF variant in a large family with a dominantly‐inherited dysferlinopathy

Is newborn screening for Duchenne muscular dystrophy ethically justifiable?

Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred

Clinical utility gene card for: Nemaline myopathy – update 2015

Diagnosis and etiology of congenital muscular dystrophy: We are halfway there

Early onset chromosome 14-linked distal myopathy (Laing)

Dominant Mutations in KBTBD13, a Member of the BTB/Kelch Family, Cause Nemaline Myopathy with Cores

Novel MYH7 mutation associated with mild myopathy but life-threatening ventricular arrhythmias and noncompaction

CUGC for Duchenne muscular dystrophy (DMD)

Early-onset Parkinson disease caused by a mutation in CHCHD2 and mitochondrial dysfunction

Ovine congenital progressive muscular dystrophy (OCPMD) is a model of TNNT1 congenital myopathy

Three novel mutations and two variants in the gene for Cu/Zn superoxide dismutase in familial amyotrophic lateral sclerosis

STRetch

Snapback SSCP analysis: Engineered conformation changes for the rapid typing of known mutations

RFC1 in an Australasian neurological disease cohort: extending the genetic heterogeneity and implications for diagnostics

A new dominant distal myopathy affecting posterior leg and anterior upper limb muscles

Motor neuron diseases caused by a novel VRK1 variant – A genotype/phenotype study

Neurogenetic fetal akinesia and arthrogryposis

Mutations in the N-terminal Actin-Binding Domain of Filamin C Cause a Distal Myopathy