ORCID Profile
0000-0003-3332-5074
Current Organisations
GNS Science Ltd
,
Concord Repatriation General Hospital
,
ANZAC Research Institute, The University of Sydney
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S0969-9961(03)00029-9
Abstract: We have studied a large Australian kindred with a dominantly inherited pure cerebellar ataxia, SCA15. The disease is characterised by a very slow rate of progression in some family members, and atrophy predominantly of the superior vermis, and to a lesser extent the cerebellar hemispheres. Repeat expansion detection failed to identify either a CAG/CTG or ATTCT/AGAAT repeat expansions segregating with the disease in this family. A genome-wide scan revealed significant evidence for linkage to the short arm of chromosome 3. The highest two-point LOD score was obtained with D3S3706 (Z = 3.4, theta = 0.0). Haplotype analysis identified recombinants that placed the SCA15 locus within an 11.6-cM region flanked by the markers D3S3630 and D3S1304. The mouse syntenic region contains two ataxic mutants, itpr1-/- and opt, affecting the inositol 1,4,5-triphosphate type 1 receptor, ITPR1 gene. ITPR1 is predominantly expressed in the cerebellar Purkinje cells. Mutation analysis from two representative affected family members excluded the coding region of the ITPR1 gene from being involved in the pathogenesis of SCA15. Thus, the itpr1-/- and opt ITPR1 mouse mutants, which each result in ataxia, are not allelic to the human SCA15 locus.
Publisher: Oxford University Press (OUP)
Date: 06-2002
DOI: 10.1093/BRAIN/AWF127
Abstract: Autosomal dominant juvenile amyotrophic lateral sclerosis (ALS) is a rare disorder and so far only one family has been reported. Genetic linkage studies mapped the disease locus to chromosome 9q34 (ALS4). The diagnosis of ALS in this family is based on the clinical signs with almost exclusively lower motor neurone pathology in combination with less prominent pyramidal tract signs. Atypical features include normal life expectancy, the absence of bulbar involvement and the symmetrical distal distribution of atrophy and weakness. We performed a molecular genetic study in three families that we had diagnosed as having distal hereditary motor neuronopathy, i.e. distal spinal muscular atrophy or spinal Charcot-Marie-Tooth syndrome, and found linkage to the ALS4 locus. The clinical phenotype in these three families, of different geographic origin (Austria, Belgium and England), is strikingly similar to the autosomal dominant juvenile ALS family except for a younger onset age in two of the distal hereditary motor neuronopathy families. These data suggest that ALS4 and distal hereditary motor neuronopathy with pyramidal tract signs may be one and the same disorder.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2007
DOI: 10.1007/S00439-007-0348-9
Abstract: The motor neuron diseases (MND) are a group of related neurodegenerative diseases that cause the relative selective progressive death of motor neurons. These diseases range from slowly progressive forms including hereditary motor neuropathy (HMN), to the rapidly progressive disorder amyotrophic lateral sclerosis (ALS). There is clinical and genetic overlap among these MNDs, implicating shared pathogenic mechanisms. We recruited a large family with a MND that was previously described as juvenile ALS and distal HMN. We identified a novel MND/HMN locus on chromosome 7q34-q36 following a genome-wide scan for linkage in this family. The disease causing mutation maps to a 26.2 cM (12.3 Mb) interval flanked by D7S2513 and D7S637 on chromosome 7q34-q36. Recombinant haplotype analysis including unaffected in iduals suggests that the refined candidate interval spans 14.3 cM (6.3 Mb) flanked by D7S2511 and D7S798. One gene in the candidate interval, CDK5, was selected for immediate mutation analysis based upon its known association with an ALS-like phenotype in mice however, no mutations were identified. Identification of genes causing familial MND will lead to a greater understanding of the biological basis of both familial and sporadic motor neuron degeneration including ALS.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.JACC.2009.11.016
Abstract: This study describes a genome-wide linkage analysis of a large family with clinically heterogeneous hypertrophic cardiomyopathy (HCM). Familial HCM is a disorder characterized by genetic heterogeneity. In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that other genes may be involved. Clinical evaluation, including clinical history, physical examination, electrocardiography, and 2-dimensional echocardiography, was performed, and blood was collected from family members (n = 23) for deoxyribonucleic acid analysis. The family was genotyped with markers from the 10-cM AB PRISM Human Linkage mapping set (Applied Biosystems, Foster City, California), and 2-point linkage analysis was performed. Affected family members showed marked clinical ersity, ranging from asymptomatic in iduals to those with syncope, heart failure, and premature sudden death. The disease locus for this family was mapped to chromosome 1q42.2-q43, near the marker D1S2850 (logarithm of odds ratio = 2.82, theta = 0). A missense mutation, Ala119Thr, in the alpha-actinin-2 (ACTN2) gene was identified that segregated with disease in the family. An additional 297 HCM probands were screened for mutations in the ACTN2 gene using high-resolution melt analysis. Three causative ACTN2 mutations, Thr495Met, Glu583Ala, and Glu628Gly, were identified in an additional 4 families (total 1.7%) with HCM. This is the first genome-wide linkage analysis that shows mutations in ACTN2 cause HCM. Mutations in genes encoding Z-disk proteins account for a small but significant proportion of genotyped HCM families.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.PEP.2015.01.006
Abstract: Lectin-like transcript 1 (LLT1, gene clec2d) was identified to be a ligand for the single human NKR-P1 receptor present on NK and NK-T lymphocytes. Naturally, LLT1 is expressed on the surface of NK cells, stimulating IFN-γ production, and is up-regulated upon activation of other immune cells, e.g. TLR-stimulated dendritic cells and B cells or T cell receptor-activated T cells. While in normal tissues LLT1:NKR-P1 interaction (representing an alternative "missing-self" recognition system) play an immunomodulatory role in regulation of crosstalk between NK and antigen presenting cells, LLT1 is upregulated in glioblastoma cells, one of the most lethal tumors, where it acts as a mediator of immune escape of glioma cells. Here we report transient expression and characterization of soluble His176Cys mutant of LLT1 ectodomain in an eukaryotic expression system of human suspension-adapted HEK293S GnTI(-) cell line with uniform N-glycans. The His176Cys mutation is critical for C-type lectin-like domain stability, leading to the reconstruction of third canonical disulfide bridge in LLT1, as shown by mass spectrometry. Purified soluble LLT1 is homogeneous, deglycosylatable and forms a non-covalent homodimer whose dimerization is not dependent on presence of its N-glycans. As a part of production of soluble LLT1, we have adapted HEK293S GnTI(-) cell line to growth in suspension in media facilitating transient transfection and optimized novel high cell density transfection protocol, greatly enhancing protein yields. This transfection protocol is generally applicable for protein production within this cell line, especially for protein crystallography.
Publisher: Wiley
Date: 20-08-2012
DOI: 10.1002/MUS.23346
Publisher: Springer Science and Business Media LLC
Date: 05-1996
DOI: 10.1038/NG0596-101
Abstract: Hereditary sensory neuropathy type I (HSN-I, also known as hereditary sensory and autonomic neuropathy type I (HSAN-I), or hereditary sensory radicular neuropathy) is an autosomal dominant disorder that is the most common of a group of degenerative disorders of sensory neurons. HSN-I was initially recognized as a disease that produced mutilating ulceration leading to utation of digits (Fig. 1). It was given names such as familial ulcers with mutilating lesions of the extremities and perforating ulcers with osseous atrophy. The disease involves a progressive degeneration of dorsal root ganglion and motor neurons, leading to distal sensory loss and later distal muscle wasting and weakness and variable neural deafness. Sensory deficits include loss of all modalities, particularly loss of sensation to pain and temperature. Skin injuries may lead to chronic skin ulcers, osteomyelitis, and extrusion of bone fragments, especially the metatarsals. Onset of symptoms is in the second or later decades. We undertook a genome screen using linkage analysis in four Australian HSN-I kindreds. We now show that the HSN1 gene maps to an 8-centiMorgan (cM) region flanked by D9S318 and D9S176 on chromosome 9q22.1-q22.3. Multipoint linkage analysis suggests a most likely location at D9S287, within a 4.9-cM confidence interval.
Publisher: Wiley
Date: 29-03-2013
DOI: 10.1002/MUS.23743
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.CLINPH.2013.11.004
Abstract: We investigated peripheral nerve function in X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), and considered the functional consequences of mutant connexin-32. Twelve subjects (9 female, 3 male) were assessed clinically, by nerve conduction and excitability studies. A model of myelinated axon was used to clarify the contributing changes. All subjects had abnormal nerve conduction. Excitability studies on median nerve axons showed greater threshold changes to hyperpolarising currents, with "fanning out" in threshold electrotonus, and modest changes in the recovery cycle. Modelling suggested shortening of internodal length, increase in nodal fast potassium currents, shift of the voltage activation hyperpolarisation-activated cyclic-nucleotide-gated channels, and axonal hyperpolarisation. Plotting threshold versus extent of hyperpolarising threshold change in threshold electrotonus distinguished the CMTX1 patients from other chronic demyelinating neuropathies reported in the literature except hereditary neuropathy with pressure palsies (HNPP). Some measures of axonal excitability are similar in CMTX1 and HNPP (though not the recovery cycle), but they differ from those in other chronic demyelinating neuropathies. The findings in CMTX1 are consistent with known pathology, but are not correlated to neuropathy severity. The findings in CMTX1 could be largely the result of morphological alterations, rather than plasticity in channel expression or distribution.
Publisher: Wiley
Date: 14-09-2018
DOI: 10.1002/MDS.106
Publisher: Wiley
Date: 03-2016
DOI: 10.1111/JNS.12160
Abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene have been found to cause X-linked dominant CMT type 6 (CMTX6). This study identified the p.R158H PDK3 mutation after screening 67 probable X-linked CMT families. The mutation fully segregated with the phenotype, and genotyping the family indicated the mutation arose on a different haplotype compared with the original Australian CMTX6 family. Results of bisulphite sequencing suggest that methylated deamination of a CpG dinucleotide may cause the recurrent p.R158H mutation. The frequency of the p.R158H PDK3 mutation in Koreans is very rare. Magnetic resonance imaging revealed fatty infiltration involving distal muscles in the lower extremities. In addition, fatty infiltrations were predominantly observed in the soleus muscles, with a lesser extent in tibialis anterior muscles. This differs from demyelinating CMT1A patients and is similar to axonal CMT2A patients. The clinical, neuroimaging, and electrophysiological findings from a second CMTX6 family with the p.R158H PDK3 mutation were similar to the axonal neuropathy reported in the Australian family.
Publisher: Oxford University Press (OUP)
Date: 05-06-2009
DOI: 10.1093/BRAIN/AWP115
Publisher: Oxford University Press (OUP)
Date: 02-2007
DOI: 10.1373/CLINCHEM.2006.080010
Abstract: Background: X-linked Charcot-Marie-Tooth type 1 disease has been associated with 280 mutations in the GJB1 [gap junction protein, beta 1, 32kDa (connexin 32, Charcot-Marie-Tooth neuropathy, X-linked)] gene. High-resolution melting analysis with an automated instrument can be used to scan DNA for alterations, but its use in X-linked disorders has not been described. Methods: A 96-well LightScanner for high resolution melting analysis was used to scan licons of the GJB1 gene. All mutations reported in this study had been confirmed previously by sequence analysis. DNA s les were lified with the double-stranded DNA-binding dye LC Green Plus. Melting curves were analyzed as fluorescence difference plots. The shift and curve shapes of melting profiles were used to distinguish controls from patient s les. Results: The method detected each of the 23 mutations used in this study. Eighteen known mutations provided validation of the high-resolution melting method and a further 5 mutations were identified in a blind study. Altered fluorescence difference curves for all the mutations were easily distinguished from the wild-type melting profile. Conclusion: High-resolution melting analysis is a simple, sensitive, and cost-efficient alternative method to scan for gene mutations in the GJB1 gene. The technology has the potential to reduce sequencing burden and would be suitable for mutation screening of exons of large multiexon genes that have been discovered to be associated with Charcot Marie Tooth neuropathy.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2004
DOI: 10.1007/S10048-004-0185-0
Abstract: Dominantly inherited sensory neuropathy (HSNI) is a degenerative disorder of sensory neurons characterized predominantly by sensory loss with mild motor impairment. Recently our group identified a locus on chromosome 3p for a new form of HSNI associated with cough and gastroesophageal reflux (GER). Haplotype analysis in a second family refined the interval to a 3.4-cM region that includes the candidate genes TOP2B and SLC4A7. The genes TOP2B and SLC4A7 and five other characterized genes that map within the critical interval have been investigated and excluded from having a pathogenic role in HSNI with cough and GER. Two novel single nucleotide polymorphisms were identified however both changes were observed in affected and non-affected in iduals, suggesting that they have no relation to the disease. We have used the resources of the Human Genome Project to report a transcript map of the region on chromosome 3p24 containing the HSNI with cough and GER locus.
Publisher: Springer Science and Business Media LLC
Date: 05-03-2010
Publisher: Wiley
Date: 13-01-2016
DOI: 10.1002/ANA.24575
Publisher: Oxford University Press (OUP)
Date: 19-09-2020
Publisher: Oxford University Press (OUP)
Date: 30-12-2011
DOI: 10.1093/HMG/DDR612
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.
Publisher: Elsevier BV
Date: 08-2023
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1086/377591
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-04-2018
DOI: 10.1212/WNL.0000000000005479
Abstract: To describe in detail the clinical profile of Charcot-Marie-Tooth disease subtype 3 (CMTX3) to aid appropriate genetic testing and rehabilitative therapy. We reviewed the clinical and neurophysiologic profile and CMT Pediatric Scale (CMTPedS) assessments of 11 children with CMTX3. Compared with the more common forms of CMT, CMT1A and CMTX, CMTX3 was characterized by early onset with early and progressive hand weakness. Most affected children were symptomatic within the first 2 years of life. The most common presentation was foot deformity in the first year of life. CMTPedS analysis in these children revealed that CMTX3 progressed more rapidly (4.3 ± 4.1 points over 2 years, n = 7) than CMT1A and CMTX1. Grip strength in affected boys was 2 SDs below age- and sex-matched normative reference values ( z score −2.05 ± 1.32) in the second decade of life. The most severely affected in idual was wheelchair bound at 14 years of age, and 2 in iduals had no movement in the small muscles of the hand in the second decade of life. Nerve conduction studies showed a demyelinating sensorimotor neuropathy with motor conduction velocity ≤23 m/s. CMTX3 had an earlier onset, severe hand weakness, and more rapidly progressive disability compared to the more common forms of CMT. Understanding the unique phenotype of CMTX3 is essential for directing genetic testing because the CMTX3 insertion will not be seen on a routine microarray or neuromuscular gene panel. Early diagnosis will enable rehabilitation to be started early in this rapidly progressive neuropathy.
Publisher: Springer Science and Business Media LLC
Date: 18-12-2019
DOI: 10.1038/S41598-019-55875-4
Abstract: EGR2 (early growth response 2) is a crucial transcription factor for the myelination of the peripheral nervous system. Mutations in EGR2 are reported to cause a heterogenous spectrum of peripheral neuropathy with wide variation in both severity and age of onset, including demyelinating and axonal forms of Charcot-Marie Tooth (CMT) neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3), and congenital hypomyelinating neuropathy (CHN/CMT4E). Here we report a sporadic de novo EGR2 variant, c.1232A G (NM_000399.5), causing a missense p.Asp411Gly substitution and discovered through whole-exome sequencing (WES) of the proband. The resultant phenotype is severe demyelinating DSN with onset at two years of age, confirmed through nerve biopsy and electrophysiological examination. In silico analyses showed that the Asp411 residue is evolutionarily conserved, and the p.Asp411Gly variant was predicted to be deleterious by multiple in silico analyses. A luciferase-based reporter assay confirmed the reduced ability of p.Asp411Gly EGR2 to activate a PMP22 (peripheral myelin protein 22) enhancer element compared to wild-type EGR2. This study adds further support to the heterogeneity of EGR2-related peripheral neuropathies and provides strong functional evidence for the pathogenicity of the p.Asp411Gly EGR2 variant.
Publisher: Elsevier BV
Date: 12-2012
Publisher: Springer Netherlands
Date: 2009
DOI: 10.1007/978-90-481-2813-6_13
Abstract: Classification of neuropathies into Charcot-Marie-Tooth syndrome (CMT, hereditary motor and sensory neuropathy) or purely motor neuropathies is relatively easy in single patients but subtle sensory findings can vary in different affected in iduals in a family. We examined the extent of sensory involvement in different in iduals in two new X-linked neuropathy syndromes (CMTX3 and dSMAX) and in some dominantly inherited mainly motor neuropathies. CMTX3 is a mild X- linked recessive CMT phenotype linked to Xq26-28. dSMAX (distal spinal muscular atrophy linked to Xq13-21). We describe a new family linked to this locus that has some sensory findings which could also be described as a motor and sensory neuropathy i.e. a form of CMT. In our dominant distal hereditary motor neuropathy (HMN) family linked to chromosome 7 (dHMN1) we also found some affected in iduals with sensory signs as well as reduced sensory action potentials. In reported HMN families with known mutations in GARS, SETX, HSPB1 and HSPB8 genes and in many of our HMN families with unknown gene mutations, there is sensory involvement producing a CMT phenotype in some in iduals. These disorders do not easily fit into traditional hereditary neuropathy classifications and should be recognised as CMT/HMN overlap syndromes. Recognition of overlap syndromes may assist development of more accurate gene screening paradigms.
Publisher: Springer Science and Business Media LLC
Date: 22-04-2019
DOI: 10.1007/S10048-019-00576-3
Abstract: Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.48-Mb interval on chromosome 14q32.11-q32.33, flanked by the markers rs2124843 and rs4983409. Whole exome sequencing identified two non-synonymous variants (p.T40P and p.H915Y) in the AHNAK2 gene that segregated with the disease in the family. Pathogenic predictions indicated that p.T40P is the likely causative allele. Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed significantly reduced mRNA and protein levels. AHNAK2 binds directly to periaxin which is encoded by the PRX gene, and PRX mutations are associated with another form of AR-CMT (CMT4F). The altered expression of mutant AHNAK2 may disrupt the AHNAK2-PRX interaction in which one of its known functions is to regulate myelination.
Publisher: Hindawi Limited
Date: 03-2015
DOI: 10.1002/HUMU.22744
Abstract: The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole-exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791G>T, p.Arg264Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases.
Publisher: Cold Spring Harbor Laboratory
Date: 17-08-2022
DOI: 10.1101/2022.08.16.504208
Abstract: Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and 4 disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene ( UBE3C ) and forms a novel gene-intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion ( UBE3C-IF ) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild type full length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic C. elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene-intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2016
DOI: 10.1007/S00439-016-1720-4
Abstract: Distal hereditary motor neuropathies predominantly affect the motor neurons of the peripheral nervous system leading to chronic disability. Using whole genome sequencing (WGS) we have identified a novel structural variation (SV) within the distal hereditary motor neuropathy locus on chromosome 7q34-q36.2 (DHMN1). The SV involves the insertion of a 1.35 Mb DNA fragment into the DHMN1 disease locus. The source of the inserted sequence is 2.3 Mb distal to the disease locus at chromosome 7q36.3. The insertion involves the duplication of five genes (LOC389602, RNF32, LMBR1, NOM1, MNX1) and partial duplication of UBE3C. The genomic structure of genes within the DHMN1 locus are not disrupted by the insertion and no disease causing point mutations within the locus were identified. This suggests the novel SV is the most likely DNA mutation disrupting the DHMN1 locus. Due to the size and position of the DNA insertion, the gene(s) directly affected by the genomic re-arrangement remains elusive. Our finding represents a new genetic cause for hereditary motor neuropathies and highlights the growing importance of interrogating the non-coding genome for SV mutations in families which have been excluded for genome wide coding mutations.
Publisher: American Thoracic Society
Date: 15-04-2010
Publisher: Springer Science and Business Media LLC
Date: 07-2008
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.NMD.2010.02.016
Abstract: Mutations in dynamin-2 (DNM2) cause autosomal dominant centronuclear myopathy (CNM). We report a series of 12 patients from eight families with CNM in whom we have identified a number of novel features that expand the reported clinicopathological phenotype. We identified two novel and five recurrent missense mutations in DNM2. Early clues to the diagnosis include relative weakness of neck flexors, external ophthalmoplegia and ptosis, although these are not present in all patients. Pes cavus was present in two patients, and in another two members of one family there was mild slowing of nerve conduction velocities. Whole-body MRI examination in two children and one adult revealed a similar pattern of involvement of selective muscles in head (lateral pterygoids), neck (extensors), trunk (paraspinal) and upper limbs (deep muscles of forearm). Findings in lower limbs and pelvic region were similar to that previously reported in adults with DNM2 mutations. Two patients presented with dystrophic changes as the predominant pathological feature on muscle biopsies one of whom had a moderately raised creatine kinase, and both patients were initially diagnosed as congenital muscular dystrophy. DNM2 mutation analysis should be considered in patients with a suggestive clinical phenotype despite atypical histopathology, and MRI findings can be used to guide genetic testing. Subtle neuropathic features in some patients suggest an overlap with the DNM2 neuropathy phenotype. Missense mutations in the C-terminal region of the PH domain appear to be associated with a more severe clinical phenotype evident from infancy.
Publisher: Wiley
Date: 14-01-2015
DOI: 10.1002/MGG3.126
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-02-2005
Publisher: Oxford University Press (OUP)
Date: 07-01-2013
DOI: 10.1093/HMG/DDS557
Publisher: VM Media SP. zo.o VM Group SK
Date: 11-08-2021
Publisher: Mary Ann Liebert Inc
Date: 06-2003
DOI: 10.1089/109065703322146821
Abstract: Alterations in gene copy number have been shown to cause disease in humans. Two of the most common inherited peripheral neuropathies, Charcot-Marie-Tooth 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), are two such diseases resulting from alteration in gene copy number of the dosage sensitive peripheral myelin protein 22 (PMP22) gene. Many complicated and laborious diagnostic tests exist for the diagnosis of these diseases. The aim of our study was to develop the first quantitative multiplex real-time PCR assay for the diagnosis of CMT1A and HNPP. A total of 160 in iduals who were known to have CMT1A, HNPP, or were normal from previous testing were assayed by our multiplex real-time PCR method. The results confirmed the previously determined gene copy number of all patient and control in iduals tested. The range of ratio values between the disease and control groups were easily defined. The assay is accurate, simple, and cost effective and can detect a 50% change in gene copy number. This represents an ideal assay for any small diagnostic laboratory.
Publisher: Wiley
Date: 16-03-2022
DOI: 10.1002/MGG3.1923
Abstract: Heterozygous KMT2B variants are a common cause of dystonia. A novel synonymous KMT2B variant, c.5073C T (p.Gly1691=) was identified in an in idual with childhood‐onset progressive dystonia. The splicing impact of c.5073C T was assessed using an in vitro exon‐trapping assay. The genomic region of KMT2B exons 23–26 was cloned into the pSpliceExpress plasmid between exon 2 and 3 of the rat Ins2 gene. The c.5073C T variant was then introduced through site‐directed mutagenesis. The KMT2B wild‐type and c.5073C T plasmids were transfected separately into HeLa cells and RNA was extracted 48 hours after transfection. The RNA was reverse transcribed to produce cDNA, which was PCR lified using primers annealing to the flanking rat Ins2 sequences. Sanger sequencing of the PCR products revealed that c.5073C T caused a novel splice donor site and therefore a 5‐bp deletion of KMT2B exon 23 in mature mRNA, leading to a coding frameshift and premature stop codon (p.Lys1692AsnfsTer7). To our knowledge, this is the first report of a KMT2B synonymous variant associated with dystonia. Reassessment of synonymous variants may increase diagnostic yield for inherited disorders including monogenic dystonia. This is of clinical importance, given the generally favourable response to deep brain stimulation for KMT2B ‐related dystonia.
Publisher: Elsevier BV
Date: 03-2010
Publisher: Springer Science and Business Media LLC
Date: 16-07-2014
DOI: 10.1007/S10048-014-0414-0
Abstract: The cytoplasmic dynein heavy chain (DYNC1H1) gene has been increasingly associated with neurodegenerative disorders including axonal Charcot-Marie-Tooth disease (CMT2), intellectual disability and malformations of cortical development. In addition, evidence from mouse models (Loa, catabolite repressor-activator (Cra) and Sprawling (Swl)) has shown that mutations in Dync1h1 cause a range of neurodegenerative phenotypes with motor and sensory neuron involvement. In this current study, we examined the possible contribution of other cytoplasmic dynein subunits that bind to DYNC1H1 as a cause of inherited peripheral neuropathy. We focused on screening the cytoplasmic dynein intermediate, light intermediate and light chain genes in a cohort of families with inherited peripheral neuropathies. Nine genes were screened and ten variants were detected, but none was identified as pathogenic, indicating that cytoplasmic dynein intermediate, light intermediate and light chains are not a cause of neuropathy in our cohort.
Publisher: Springer Science and Business Media LLC
Date: 03-1994
DOI: 10.1038/NG0394-263
Abstract: Hereditary neuropathy with liability to pressure palsies (HNPP) has been a associated with a deletion of 1.5 megabases of chromosome 17p. One of four biopsy proven HNPP families that we have studied did not possess this deletion. As the deleted DNA region includes the coding region for a peripheral myelin gene (PMP22), we used single strand conformation analysis to examine this gene for mutations in the non-deleted HNPP family. An abnormal fragment in exon 1 was identified, and sequencing revealed a two base pair deletion in all affected family members. The deletion results in a frame shift, providing strong evidence that this gene has an important role in the pathogenesis of the disease.
Publisher: Hindawi Limited
Date: 28-11-2013
DOI: 10.1155/2013/495873
Abstract: Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of disorders affecting both motor and sensory neurons in the peripheral nervous system. Mutations in the MFN2 gene cause an axonal form of CMT, CMT2A. The V705I variant in MFN2 has been previously reported as a disease-causing mutation in families with CMT2. We identified an affected index patient from an Australian multigenerational family with the V705I variant. Segregation analysis showed that the V705I variant did not segregate with the disease phenotype and was present in control in iduals with an allele frequency of 4.4%. We, therefore, propose that the V705I variant is a polymorphism and not a disease-causing mutation as previously reported.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2015
Publisher: Oxford University Press (OUP)
Date: 2018
DOI: 10.1093/BRAIN/AWY184
Publisher: Oxford University Press (OUP)
Date: 14-03-2017
Publisher: Oxford University Press (OUP)
Date: 27-04-2017
DOI: 10.1093/BRAIN/AWX095
Publisher: Springer Science and Business Media LLC
Date: 05-06-2020
DOI: 10.1038/S41598-020-66266-5
Abstract: Charcot-Marie-Tooth (CMT) is a group of inherited diseases clinically and genetically heterogenous, characterised by length dependent degeneration of axons of the peripheral nervous system. A missense mutation (p.R158H) in the pyruvate dehydrogenase kinase 3 gene ( PDK3 ) has been identified as the genetic cause for an X-linked form of CMT (CMTX6) in two unrelated families. PDK3 is one of four PDK isoenzymes that regulate the activity of the pyruvate dehydrogenase complex (PDC). The balance between kinases (PDKs) and phosphatases (PDPs) determines the extend of oxidative decarboxylation of pyruvate to generate acetyl CoA, critically linking glycolysis and the energy producing Krebs cycle. We had shown the p.R158H mutation causes hyperactivity of PDK3 and CMTX6 fibroblasts show hyperphosphorylation of PDC, leading to reduced PDC activity and ATP production. In this manuscript we have generated induced pluripotent stem cells (iPSCs) by re-programming CMTX6 fibroblasts (iPSC CMTX6 ). We also have engineered an isogenic control (iPSC isogenic ) and demonstrated that genetic correction of the p.R158H mutation reverses the CMTX6 phenotype. Patient-derived motor neurons (MN CMTX6 ) show increased phosphorylation of the PDC, energy metabolism defects and mitochondrial abnormalities, including reduced velocity of trafficking mitochondria in the affected axons. Treatment of the MN CMTX6 with a PDK inhibitor reverses PDC hyperphosphorylation and the associated functional deficits founds in the patient motor neurons, demonstrating that the MN CMTX6 and MN isogenic motor neurons provide an excellent neuronal system for compound screening approaches to identify drugs for the treatment of CMTX6.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2021
DOI: 10.1007/S10048-021-00650-9
Abstract: The second most common form of Charcot-Marie-Tooth neuropathy (CMT), X-linked CMT type X1 (CMTX1), is caused by coding and non-coding mutations in the gap junction beta 1 ( GJB1 ) gene. The non-coding GJB1 c.-103C T mutation (NM_000166.5) has been reported to cause CMTX1 in multiple families. This study assessed the internal ribosomal entry site (IRES) activity previously reported for the rat Gjb1 P2 5’ untranslated region (UTR). Using a bicistronic assay and transfecting RT4 Schwann cells, IRES activity of the human GJB1 P2 5’ UTR was compared to the GJB1 P2 5’ UTR containing either the c.-103C T mutation or the non-pathogenic c.-102G A variant. No differences in GJB1 P2 5’ UTR IRES activity were observed between the negative control, the wild-type P2 5’ UTR, the c.-103C T 5’ UTR or the c.-102G A 5’ UTR, irrespective of the GJB1 intron being present ( p = .429 with intron, and p = .865 without). A theoretical c.-131A G variant was predicted to result in the same RNA secondary structure as the GJB1 c.-103C T P2 5’ UTR. However, no significant difference was observed between expression from the wild-type GJB1 P2 5’ UTR and the GJB1 c.-131A G variant ( p = .688). Deletion of the conserved region surrounding the c.-103C T mutation (c.-108_-103del) resulted in significantly higher expression than the c.-103C T mutation alone ( p = .019), suggesting that the conserved c.-108_-103 region was not essential for translation. The reporter assays in this study do not recapitulate the previously reported GJB1 IRES activity and suggest an alternate pathogenic mechanism for the c.-103C T CMTX1 non-coding mutation.
Publisher: eLife Sciences Publications, Ltd
Date: 11-05-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-01-2009
DOI: 10.1212/01.WNL.0000339483.86094.A5
Abstract: To clinically characterize and map the gene locus in a three-generation family with an X-linked adult-onset distal hereditary motor neuropathy. Microsatellite markers spanning the juvenile distal spinal muscular atrophy (DSMAX) locus were genotyped and analyzed using genetic linkage analysis. The promoter, untranslated and coding region of the gap junction beta1 (GJB1) gene was sequenced. Nine positional candidate genes were screened for disease mutations using high-resolution melt (HRM) analysis. The family showed significant linkage to markers on chromosome Xq13.1-q21. Haplotype construction revealed a disease-associated haplotype between the markers DXS991 and DX5990. Sequence analysis excluded pathogenic changes in the coding and promoter regions of the GJB1 gene. Additional fine mapping in the family refined the DSMAX locus to a 1.44-cM interval between DXS8046 and DXS8114. HRM analysis did not identify disease-associated mutations in the coding region of nine candidate genes. We have identified a family with adult-onset distal hereditary motor neuropathy that refines the locus reported for juvenile distal spinal muscular atrophy (DSMAX) on chromosome Xq13.1-q21. Exclusion of mutations in the coding and regulatory region of the GJB1 gene eliminated the CMTX1 locus as a cause of disease in this family. Nine positional candidate genes in the refined interval underwent mutation analysis and were eliminated as the pathogenic cause of DSMAX in this family. The syndrome in this family may be allelic to the juvenile distal spinal muscular atrophy first reported at this locus.
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0960-8966(02)00015-9
Abstract: Recently point mutations in the SPTLC1 subunit of serine palmitoyltransferase have been shown to cause the common form of dominant hereditary sensory neuropathy (HSN1). Serine palmitoyltransferase (SPT) is a heterodimeric molecule made up of two subunits, SPTLC1 and SPTLC2. Twelve index patients from families with presumed genetic sensory neuropathies were screened for SPTLC2 mutations. These families comprised six multigenerational families, including two previously reported families not linked to the SPTLC1 locus on chromosome 9 and one multigenerational family with a complicated hereditary sensory neuropathy syndrome with associated palmar plantar keratosis, ataxia and spastic paraplegia. The remaining families included one consanguineous family with presumed recessive HSN with two affected siblings, one case of congenital sensory neuropathy and four sporadic cases with adult onset sensory neuropathy. No mutations in the SPTLC2 gene were found in any family. These results suggest that SPTLC2 mutations are not a common cause for genetic sensory neuropathies.
Publisher: Wiley
Date: 20-08-2201
Publisher: MDPI AG
Date: 14-08-2020
Abstract: Y-box binding protein-1 (YB-1) is a multifunctional oncoprotein that has been shown to regulate proliferation, invasion and metastasis in a variety of cancer types. We previously demonstrated that YB-1 is overexpressed in mesothelioma cells and its knockdown significantly reduces tumour cell proliferation, migration, and invasion. However, the mechanisms driving these effects are unclear. Here, we utilised an unbiased RNA-seq approach to characterise the changes to gene expression caused by loss of YB-1 knockdown in three mesothelioma cell lines (MSTO-211H, VMC23 and REN cells). Bioinformatic analysis showed that YB-1 knockdown regulated 150 common genes that were enriched for regulators of mitosis, integrins and extracellular matrix organisation. However, each cell line also displayed unique gene expression signatures, that were differentially enriched for cell death or cell cycle control. Interestingly, deregulation of STAT3 and p53-pathways were a key differential between each cell line. Using flow cytometry, apoptosis assays and single-cell time-lapse imaging, we confirmed that MSTO-211H, VMC23 and REN cells underwent either increased cell death, G1 arrest or aberrant mitotic ision, respectively. In conclusion, this data indicates that YB-1 knockdown affects a core set of genes in mesothelioma cells. Loss of YB-1 causes a cascade of events that leads to reduced mesothelioma proliferation, dependent on the underlying functionality of the STAT3 53-pathways and the genetic landscape of the cell.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-11-2001
Abstract: A kindred is described with a dominantly inherited "pure" cerebellar ataxia in which the currently known spinocerebellar ataxias have been excluded. In the eight subjects studied, a notable clinical feature is slow progression, with the three least affected having only a mild degree of gait ataxia after three or more decades of disease duration. Pending an actual chromosomal locus discovery, the name spinocerebellar ataxia (SCA)15 is expectantly applied.
Publisher: Elsevier BV
Date: 06-2004
DOI: 10.1086/421054
Publisher: BMJ
Date: 08-2007
Publisher: Wiley
Date: 23-03-2018
DOI: 10.1002/MGG3.390
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-03-2022
Abstract: More than 50 neurological and neuromuscular diseases are caused by short tandem repeat (STR) expansions, with 37 different genes implicated to date. 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 assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of STR sites, from a list of predetermined candidates. This correctly diagnoses all in iduals in a small cohort ( n = 37) including patients with various neurogenetic diseases ( n = 25). Targeted long-read sequencing solves large and complex STR expansions that confound established molecular tests and short-read sequencing and identifies noncanonical STR motif conformations and internal sequence interruptions. We observe a ersity of STR alleles of known and unknown pathogenicity, suggesting that long-read sequencing will redefine the genetic landscape of repeat disorders. Last, we show how the inclusion of pharmacogenomic genes as secondary ReadUntil targets can further inform patient care.
Publisher: Oxford University Press (OUP)
Date: 22-03-2017
DOI: 10.1093/BRAIN/AWX058
Publisher: Elsevier BV
Date: 11-1997
Abstract: Misalignment between the two elements of the CMT1A-REP binary repeat on chromosome 17p11.2-p12 causes two inherited peripheral neuropathies, Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies. This binary repeat contains repetitive DNA elements that include LINES, SINES, medium reiteration frequency repeats, and a transposon-like element. The COX10 gene has been mapped 10 kb centromeric to the distal CMT1A-REP element, and a portion of this gene is present in both the proximal and the distal CMT1A-REP elements. We report the isolation and characterization of a novel cDNA (C170RF1), which maps centromeric to and partially within the proximal CMT1A-REP element. Part of C170RF1 is transcribed from the opposite strand of the COX10 partial gene duplication present in the proximal CMT1A-REP element. This finding shows that C170RF1 and COX10 are being transcribed from opposite strands of identical DNA sequences that are separated by 1.5 Mb in the genome. RT-PCR analysis showed the proximal transcript was expressed in skeletal muscle. Sequence analysis identified an open reading frame encoding a 199-amino-acid protein. Zoo blot analysis showed that the transcript is conserved in nonhuman primates. The presence of a binary repeat contributes to the instability of this region of chromosome 17, yet two CMT1A-REP elements are present in the chimpanzee and all human populations. The presence of expressed sequences in both elements of the CMT1A-REP binary repeat could explain the maintenance of this repeat in humans.
Publisher: Wiley
Date: 16-02-2016
DOI: 10.1111/CGE.12712
Abstract: The cytoplasmic dynein-dynactin genes are attractive candidates for neurodegenerative disorders given their functional role in retrograde transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) gene has been implicated in various neurodegenerative disorders, and dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of disorders including motor neuron disease, Parkinson's disease, spinobulbar muscular atrophy and hereditary spastic paraplegia. However, the involvement of other dynactin genes with inherited peripheral neuropathies (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy and Charcot-Marie-Tooth disease is under reported. We screened eight genes DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using whole-exome sequencing and high-resolution melt (HRM) analysis. Eight non-synonymous variants (including one novel variant) and three synonymous variants were identified. Four variants have been reported previously in other studies, however segregation analysis within family members excluded them from causing IPN in these families. No variants of disease significance were identified in this study suggesting the dynactin genes are unlikely to be a common cause of IPNs. However, with the ease of querying gene variants from exome data, these genes remain worthwhile candidates to assess unsolved IPN families for variants that may affect the function of the proteins.
Publisher: Springer Science and Business Media LLC
Date: 08-2003
DOI: 10.1007/S10048-003-0147-Y
Abstract: Charcot-Marie-Tooth (CMT) neuropathy is one of the most common hereditary disorders of the human peripheral nervous system. The CMT syndrome includes weakness and atrophy of distal muscles, high arched feet (pes cavus), depressed or absent deep tendon reflexes, and mild sensory loss. Dominant intermediate CMT (DI-CMT) neuropathy is a form of CMT with intermediate median motor nerve conduction velocities. We previously localized the DI-CMT locus to a 16.8-cM region on chromosome 19p12-p13.2. Extended haplotype analysis and clinical assessment of additional family members and a report of a second family linked to this locus has enabled us to narrow the candidate region to a 6-cM interval flanked by D19S558 and D19S432. Selection of positional candidate genes for screening was performed on the basis of neural expression and microarray analysis of Schwann cell differentiation in vivo. Seven candidate genes have been investigated. These include six genes localized in the original linkage interval and one in the newly refined region. They are excluded as a cause for DI-CMT neuropathy.
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2022
DOI: 10.1101/2022.05.25.493316
Abstract: Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes that ligate tRNA molecules to their cognate amino acids. Heterozygosity for missense variants or small in-frame deletions in five ARS genes causes axonal peripheral neuropathy, a disorder characterized by impaired neuronal function in the distal extremities. These variants reduce enzyme activity without significantly decreasing protein levels and reside in genes encoding homo-dimeric enzymes. These observations raise the possibility of a dominant-negative effect, in which non-functional mutant ARS subunits dimerize with wild-type ARS subunits and reduce overall ARS activity below 50%, breaching a threshold required for peripheral nerve axons. To test for these dominant-negative properties, we developed a humanized yeast assay to co-express pathogenic human alanyl-tRNA synthetase ( AARS1 ) mutations with wild-type human AARS1 . We show that multiple loss-of-function, pathogenic AARS1 variants repress yeast growth in the presence of wild-type human AARS1 . This growth defect is rescued when these variants are placed in cis with a mutation that reduces dimerization with the wild-type subunit, demonstrating that the interaction between mutant AARS1 and wild-type AARS1 is responsible for the repressed growth. This demonstrates that neuropathy-associated AARS1 variants exert a dominant-negative effect, which supports a common, loss-of-function mechanism for ARS-mediated dominant peripheral neuropathy.
Publisher: eLife Sciences Publications, Ltd
Date: 13-05-2021
DOI: 10.7554/ELIFE.65234
Abstract: We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here, we advanced this model system and identified a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single-cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in human lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-02-2003
DOI: 10.1212/01.WNL.0000048561.61921.71
Abstract: To determine whether Charcot-Marie-Tooth (CMT) with pyramidal features is genetically distinct from other dominantly inherited axonal neuropathies, the authors examined all chromosomal loci and genes for axonal CMT. Two families were identified with an axonal CMT phenotype with distal wasting, weakness, pes cavus, sensory loss, and mild pyramidal signs (including extensor plantar responses, mild increase in tone, and preserved or increased reflexes but no spastic gait). Linkage studies excluded CMT2A, 2B, 2D, 2E, and 2F ALS4 and HMN2. There were no mutations in the PMP22 , MPZ/Po , or EGR2 genes.
Publisher: Hindawi Limited
Date: 09-11-2011
DOI: 10.1002/HUMU.21635
Publisher: Wiley
Date: 09-02-2009
DOI: 10.1111/J.1471-4159.2008.05846.X
Abstract: Oxidative stress is associated with the pathology of acute and chronic neurodegenerative disease. We have cloned a human neuroglobin (Nb) construct and over-expressed this protein in cultured human neuronal cells to assess whether Nb ameliorates the cellular response to experimental hypoxia-reoxygenation (H/R) injury. Parental cells transfected with a blank (pDEST40) vector responded to H/R injury with a significant decrease in cellular ATP at 5 and 24 h after insult. This was coupled with increases in the cytosolic Ca(2+), and the transition metals iron (Fe), copper (Cu), and zinc (Zn) within the cell body, as monitored simultaneously using X-ray fluorescence microprobe imaging. Parental cell viability decreased over the same time period with a approximately 4 to 5-fold increase in cell death (maximum approximately 25%) matched by an increase in caspase 3/7 activation (peaking at a 15-fold increase after 24 h) and condensation of beta-actin along axonal processes. Over-expression of Nb inhibited ATP loss and except for significant decreases in the sulfur (S), chlorine (Cl), potassium (K) and Ca(2+) contents, maintained cellular ion homeostasis after H/R insult. This resulted in increased cell viability, significantly diminished caspase activation and maintenance of the beta-actin cytoskeletal structure and receptor-mediated endocytosis. These data indicate that bolstering the cellular content of Nb inhibits neuronal cell dysfunction promoted by H/R insult through multiple protective actions including: (i) maintenance of cellular bioenergetics (ii) inhibition of Ca(2+) influx (iii) a reduction in cellular uptake of Fe, Cu and Zn at the expense of S, Cl and K and (iv) an enhancement of cell viability through inhibiting necrosis and apoptosis.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.CLINPH.2016.11.010
Abstract: The utility of quantitative muscle ultrasound as a marker of disease severity in Charcot-Marie-Tooth (CMT) disease subtypes was investigated. Muscle ultrasound was prospectively performed on 252 in idual muscles from 21 CMT patients (9 CMT1A, 8 CMTX1, 4 CMT2A) and compared to 120 muscles from 10 age and gender-matched controls. Muscle ultrasound recorded echogenicity and thickness in representative muscles including first dorsal interosseus (FDI) and tibialis anterior (TA). Muscle volume of FDI and thickness of TA correlated with MRC strength. Muscle echogenicity was significantly increased in FDI (65.05 vs 47.09 p<0.0001) and TA (89.45 vs 66.30 p<0.0001) of CMT patients. In TA, there was significantly higher muscle thickness (23 vs 18 vs 16mm p<0.0001) and lower muscle echogenicity (80 vs 95 vs 108 p<0.0001) in CMT1A compared to CMTX1 and CMT2A. This corresponded to disease severity based on muscle strength (MRC grading CMT1A vs CMTX1 vs CMT2A: 59 vs 48 vs 44 p=0.002). In CMT, quantitative muscle ultrasound of FDI and TA is a useful marker of disease severity. The current findings suggest that quantitative muscle ultrasound has potential as a surrogate marker of disease progression in future interventional trials in CMT.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-08-2005
Publisher: Elsevier BV
Date: 10-1998
Abstract: C17orf1, a gene expressed in skeletal muscle and heart, was initially isolated from a fetal brain cDNA library and localized centromeric to and partially within the proximal CMT1A-REP element. A second gene, COX10, spans the distal CMT1A-REP element, and a duplicated exon of this gene is present in the proximal CMT1A-REP element. C17orf1 includes this duplicated COX10 exon within its sequence however, the DNA strand opposite to that of the COX10 gene is utilized. We have determined the genomic organization of C17orf1 and found it to be oriented in the direction opposite to COX10. Analysis of the genomic structure of C17orf1 has revealed that it contains at least six exons and spans a length of at least 17 kb. All but one of the splice sites conform to the GT/AG rule, and in this case the splice acceptor site within intron 1 is GA instead of the expected AG. Sequencing and mapping analyses have shown that the centromeric boundary of the proximal CMT1A-REP element lies within intron 5. A 7-bp insertion, identified from genomic sequencing of cosmid clones and verified in the original cDNA clone and RT-PCR products, has extended the previously reported open reading frame from 591 to 756 bp. C17orf1 therefore encodes a 252-amino-acid protein.
Publisher: Public Library of Science (PLoS)
Date: 20-07-2016
Publisher: American Medical Association (AMA)
Date: 11-1994
DOI: 10.1001/ARCHNEUR.1994.00540230063014
Abstract: To determine whether the syndrome of benign familial neonatal convulsions in a large family was linked to markers on chromosome 20q and to study the seizure patterns in affected in iduals. A clinical and molecular biologic study of a single large family in which the probands were identical twins with benign familial neonatal convulsions. Thirteen living affected family members and 27 living unaffected family members were evaluated. Multipoint linkage analysis with use of the chromosome 20q markers CMM6 and RMR6 gave a maximum lod score of 3.13 at theta = 0.063, indicating linkage in this family. Of the 13 affected members, 10 had known neonatal seizures. Four subjects had febrile seizures, of whom only two had known neonatal seizures. Two members had afebrile seizures later, one of whom had not previously suffered neonatal or febrile seizures. The phenotypic heterogeneity in this family, with an epilepsy syndrome determined by a single gene, was striking. This suggests that molecular genetic approaches to the common forms of idiopathic epilepsy, involving patients with clinically similar phenotypes from unrelated families, may be inappropriate.
Publisher: Wiley
Date: 11-1992
Abstract: A locus for the slow conducting form of Charcot-Marie-Tooth neuropathy (CMT1A) was localised to the proximal short arm of chromosome 17, in band p11.2, distal to D17S58. Linkage studies of CMT1A in 3 large Australian families with the marker loci D17S58, D17S71, and D17S57 suggested the order, pter-CMT1A-D17S71-D17S58-centromere-D17S57. However, the estimate of the recombination fraction between CMT1A and D17S122, also assigned to p11.2, was incompatible with known map distances. The impasse was resolved when the D17S122 genotypes were revised to take into account a dosage effect due to a duplication. After correction of the genotypes, the maximum lod score between CMT1A and D17S122 increased from 0.53 at a recombination fraction of 0.3 to 34.28 at zero recombination. This result emphasizes that genotypes for markers in the p12-p11.2 region should be examined very carefully as ignoring the duplication changes the linkage results dramatically. The fact that no crossovers were found between CMT1A and D17S122 suggests that the duplication may cause the disease phenotype.
Publisher: The Company of Biologists
Date: 13-01-2020
DOI: 10.1242/DMM.041541
Abstract: ATP7A encodes a copper-transporting P-type ATPase and is one of 23 genes in which mutations produce distal hereditary motor neuropathy (dHMN), a group of diseases characterized by length-dependent axonal degeneration of motor neurons. We have generated induced pluripotent stem cell (iPSC)-derived motor neurons from a patient with the p.T994I ATP7A gene mutation as an in vitro model for X-linked dHMN (dHMNX). Patient motor neurons show a marked reduction of ATP7A protein levels in the soma when compared to control motor neurons and failed to upregulate expression of ATP7A under copper-loading conditions. These results recapitulate previous findings obtained in dHMNX patient fibroblasts and in primary cells from a rodent model of dHMNX, indicating that patient iPSC-derived motor neurons will be an important resource for studying the role of copper in the pathogenic processes that lead to axonal degeneration in dHMNX.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.NBD.2016.07.001
Abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. An X-linked form of CMT (CMTX6) is caused by a missense mutation (R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. PDK3 is one of 4 isoenzymes that negatively regulate the activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation of its first catalytic component pyruvate dehydrogenase (designated as E1). Mitochondrial PDC catalyses the oxidative decarboxylation of pyruvate to acetyl CoA and links glycolysis to the energy-producing Krebs cycle. We have previously shown the R158H mutation confers PDK3 enzyme hyperactivity. In this study we demonstrate that the increased PDK3 activity in patient fibroblasts (PDK3(R158H)) leads to the attenuation of PDC through hyper-phosphorylation of E1 at selected serine residues. This hyper-phosphorylation can be reversed by treating the PDK3(R158H) fibroblasts with the PDK inhibitor dichloroacetate (DCA). In the patient cells, down-regulation of PDC leads to increased lactate, decreased ATP and alteration of the mitochondrial network. Our findings highlight the potential to develop specific drug targeting of the mutant PDK3 as a therapeutic approach to treating CMTX6.
Publisher: Elsevier BV
Date: 10-2001
DOI: 10.1086/323743
Location: Switzerland
Location: Australia
Start Date: 2003
End Date: 2005
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2008
End Date: 2009
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2022
End Date: 2025
Funder: Marsden Fund
View Funded ActivityStart Date: 2011
End Date: 2013
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2008
End Date: 2009
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2001
End Date: 2003
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2011
End Date: 2013
Funder: National Health and Medical Research Council
View Funded Activity