ORCID Profile
0000-0002-5221-7303
Current Organisation
Royal Brisbane and Women's Hospital
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Publisher: Oxford University Press (OUP)
Date: 03-2011
DOI: 10.1530/EJE-10-0907
Abstract: The calcium-sensing receptor (CASR) is a key controller of calcium homeostasis by regulating parathyroid hormone (PTH) secretion and renal calcium reabsorption. CASR T888 is a protein kinase C (PKC) phosphorylation site in the receptor's intracellular domain that has previously been identified as a critical negative regulator of CASR downstream signaling in vitro , but whose importance in vivo is unknown. The proband presented with mild symptomatic hypocalcemia following treatment for nephrotic syndrome due to minimal change glomerulonephropathy. Laboratory tests revealed inappropriately normal PTH concentrations and relative hypercalciuria typical of autosomal dominant hypocalcemia. His asymptomatic father had similar laboratory test results. The CASR gene was sequenced. To investigate the molecular consequences of CASR T888M mutation, site-directed mutagenesis was used to modify the wild-type (wt)- CASR gene, with the resulting mutant being transfected transiently into HEK-293 cells. A novel CASR missense mutation, T888M, was identified in both cases. The CASR T888M mutant exhibited enhanced sensitivity to extracellular calcium concentration, both for intracellular calcium (Ca 2+ i ) mobilization and for ERK phosphorylation, despite having unaltered levels of cell surface expression. Furthermore, CASR T888M elicited sustained Ca 2+ i mobilization rather than high frequency Ca 2+ i oscillations, and, unlike the wt-CASR, the response was resistant to acute inhibition by the PKC activator, phorbol 12-myristate 13-acetate. The clinical and functional data provide the first genotype–phenotype correlation for a mutation at T888, indicating its critical physiological importance in CASR signaling. Thus, CASR T888 represents a functionally important, inhibitory phosphorylation site that contributes to the control of PTH secretion.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2014
Abstract: The genetic mutation resulting in osteogenesis imperfecta (OI) type V was recently characterised as a single point mutation (c.-14C T) in the 5’ untranslated region (UTR) of IFITM5 , a gene encoding a transmembrane protein with expression restricted to skeletal tissue. This mutation creates an alternative start codon and has been shown in a eukaryotic cell line to result in a longer variant of IFITM5, but its expression has not previously been demonstrated in bone from a patient with OI type V. Sanger sequencing of the IFITM5 5’ UTR was performed in our cohort of subjects with a clinical diagnosis of OI type V. Clinical data was collated from referring clinicians. RNA was extracted from a bone s le from one patient and Sanger sequenced to determine expression of wild-type and mutant IFITM5 . All nine subjects with OI type V were heterozygous for the c.-14C T IFITM5 mutation. Clinically, there was heterogeneity in phenotype, particularly in the manifestation of bone fragility amongst subjects. Both wild-type and mutant IFITM5 mRNA transcripts were present in bone. The c.-14C T IFITM5 mutation does not result in an RNA-null allele but is expressed in bone. In iduals with identical mutations in IFITM5 have highly variable phenotypic expression, even within the same family.
Publisher: The Endocrine Society
Date: 05-2021
DOI: 10.1210/JENDSO/BVAB048.431
Abstract: Background: Heterotopic ossification (HO) is a rare disease characterised by abnormal bone growth in non-osseous tissues, causing pain, immobility and impaired quality of life. Although still being elucidated, the underlying pathophysiology may relate to local macrophage-driven inflammation in response to trauma1. Case: A 35-year-old man involved in a motor vehicle accident (MVA) fractured over twenty bones (multiple vertebrae, ribs and complex open book pelvic fracture with shattered left acetabulum) with extensive soft tissue injuries requiring multiple surgeries. Past medical history included a renal calculus three years earlier. His serum corrected calcium on admission was elevated at 2.87mmol/L (2.10-2.60mmol/L). Peri-operative fluid over-resuscitation necessitated boluses of intravenous furosemide, and serum calcium transiently normalised before rapidly incrementing and peaking at 3.04 mmol/L. Serum parathyroid hormone post-operatively was inappropriately high at 9.4pmol/L (1.0–7.0pmol/L) and 25-hydroxyvitamin D low at 24nmol/L (50-150nmol/L). Oral vitamin D replacement was commenced and he received intravenous pamidronate (3x60mg infusions) which briefly restored normocalcaemia. Neck ultrasound and sestamibi scintigraphy demonstrated a left parathyroid adenoma, and he underwent parathyroidectomy. Histology revealed a single parathyroid adenoma. He has been normocalcaemic since surgery. Despite excellent overall recovery, mobility at the left hip remained restricted in all planes of movement. He could not perform simple activities such as putting on his shoe. Plain radiographs showed HO lateral to the left acetabulum, femoral head and neck, with bony bridging to the left ilium on computed tomography. Bone turnover markers (BTMs) measured eleven months post-MVA (and pamidronate) were elevated, with CTX of 750ng/L (100-600ng/L) and P1NP of 207ug/L (15-80ug/L). BTMs gradually reduced over time, plateauing two years post-MVA (CTX 480ng/L and P1NP 103ug/L). Surgery with pre-operative radiotherapy to remove the left hip HO is now planned. Discussion: This man had multiple recognised risk factors for HO, including male sex, trauma followed by immobilisation and pelvic fracture. His hyperparathyroidism may have predisposed HO development through excess calcium-phosphate product promoting soft tissue calcification. Bisphosphonates may also increase the risk2. Elevated BTMs have been demonstrated in the early phase of HO further research may elucidate whether BTMs can guide timing of surgical intervention relative to the pathophysiological processes driving HO. References: 1 Meyers C et al. Heterotopic Ossification: A Comprehensive Review. JBMR Plus 2019, 3: e10172 2 Genêt F et al. Neurological heterotopic ossification following spinal cord injury is triggered by macrophage-mediated inflammation in muscle 2015. J Pathol. 236(2):229–40
Publisher: Wiley
Date: 14-05-2021
DOI: 10.1002/AJMG.A.62257
Abstract: Multicentric carpotarsal osteolysis (MCTO) is an autosomal dominant condition characterized by carpal–tarsal abnormalities over half of affected in iduals also develop renal disease. MCTO is caused by mutations of MAFB however, there is no clear phenotype–genotype correlation. We describe the first reported family of variable MCTO phenotype due to mosaicism: the proband had classical skeletal features and renal involvement due to focal segmental glomerulosclerosis (FSGS), and the father had profound renal impairment due to FSGS, necessitating kidney transplantation. Mosaicism was first suspected in this family due to unequal allele ratios in the sequencing chromatograph of the initial blood s le of proband's father and confirmed by sequencing DNA extracted from the father's hair, collected from different bodily parts. This case highlights the need for a high index of clinical suspicion to detect low‐level parental mosaicism, as well as a potential role for MAFB mutation screening in in iduals with isolated FSGS.
Publisher: Springer Science and Business Media LLC
Date: 08-2014
DOI: 10.1007/S00198-013-2443-1
Abstract: In the last decade, huge breakthroughs in genetics-driven by new technology and different statistical approaches-have resulted in a plethora of new disease genes identified for both common and rare diseases. Massive parallel sequencing, commonly known as next-generation sequencing, is the latest advance in genetics, and has already facilitated the discovery of the molecular cause of many monogenic disorders. This article describes this new technology and reviews how this approach has been used successfully in patients with skeletal dysplasias. Moreover, this article illustrates how the study of rare diseases can inform understanding and therapeutic developments for common diseases such as osteoporosis.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2014
DOI: 10.1007/S00198-013-2465-8
Abstract: Interferon-induced transmembrane protein 5 or bone-restricted ifitm-like gene (Bril) was first identified as a bone gene in 2008, although no in vivo role was identified at that time. A role in human bone has now been demonstrated with a number of recent studies identifying a single point mutation in Bril as the causative mutation in osteogenesis imperfecta type V (OI type V). Such a discovery suggests a key role for Bril in skeletal regulation, and the completely novel nature of the gene raises the possibility of a new regulatory pathway in bone. Furthermore, the phenotype of OI type V has unique and quite ergent features compared with other forms of OI involving defects in collagen biology. Currently it appears that the underlying genetic defect in OI type V may be unrelated to collagen regulation, which also raises interesting questions about the classification of this form of OI. This review will discuss current knowledge of OI type V, the function of Bril, and the implications of this recent discovery.
Publisher: Wiley
Date: 06-10-2021
DOI: 10.1002/JBM4.10557
Abstract: Voriconazole‐associated periostitis (VAP) is an underrecognized and unpredictable side effect of long‐term voriconazole therapy. We report two cases of VAP occurring in the post‐transplant setting: a 68‐year‐old lung transplant recipient who required ongoing voriconazole therapy, in whom urinary alkalinization was used to promote fluoride excretion and minimize voriconazole‐related skeletal toxicity, and a 68‐year‐old stem‐cell transplant recipient with a high voriconazole dose requirement, identified on pharmacogenomic testing to be a CYP2C19 ultrarapid metabolizer, the dominant enzyme in voriconazole metabolism. This is the first reported case of pharmacogenomic profiling in VAP and may explain the variability in in idual susceptibility to this uncommon adverse effect. Our findings provide new insights into both the management and underlying pathophysiology of VAP. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.AJPATH.2017.05.007
Abstract: Multicentric carpal-tarsal osteolysis multicentric osteolysis, nodulosis, and arthropathy and Winchester syndromes, skeletal dysplasias characterized by carpal/tarsal and epiphyseal abnormalities, are caused by mutations in v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B (MAFB), matrix metalloproteinase (MMP) 2, and MMP14, respectively however, the underlying pathophysiology is unclear. Osteoclast-mediated osteolysis has been regarded as the main mechanism, but does not explain the skeletal distribution. We hypothesized that MAFB, MMP-2, and MMP-14 have integral roles in carpal/tarsal and epiphyseal bone development. Normal neonatal mouse forepaws were imaged by micro-computed tomography and examined histologically. Murine forepaw ossification occurred sequentially. Subarticular regions of endochondral ossification showed morphologic and calcification patterns that were distinct from archetypical physeal endochondral ossification. This suggests that two different forms of endochondral ossification occur. The skeletal sites showing the greatest abnormality in the carpal-tarsal osteolysis syndromes are regions of subarticular ossification. Thus, abnormal bone formation in areas of subarticular ossification may explain the site-specific distribution of the carpal-tarsal osteolysis phenotype. MafB, Mmp-2, and Mmp-14 were expressed widely, and tartrate-resistant acid phosphatase staining notably was absent in the subarticular regions of the cartilage anlagen and entheses at a time point most relevant to the human osteolysis syndromes. Thus, abnormal peri-articular skeletal development and modeling, rather than excessive bone resorption, may be the underlying pathophysiology of these skeletal syndromes.
No related grants have been discovered for Syndia Lazarus.