A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta

Rubinato, Elisa; Morgan, Anna; D’Eustacchio, Angela; Pecile, Vanna; Gortani, Giulia; Gasparini, Paolo; Faletra, Flavio

doi:10.1016/j.gene.2014.05.028

Cited by 42 publications

(43 citation statements)

References 7 publications

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“…P7 and P8 were born to unrelated American parents of British/Scottish and British/German origin and found to be compound heterozygous for the previously reported deletion encompassing TMEM38B exons 1 and 2 10 and a novel c.63dupT, which directly introduces a premature termination codon (p.D22X). Their father carries the deletion and their mother the c.63dupT allele.…”

Section: Molecular Studiesmentioning

confidence: 99%

“…TMEM38B mutations reported to date include an exon 4 deletion among Bedouins 8 9 , an exon 1-2 deletion in an Albanian child 10 and two point mutations in exon 4 and intron 3 in three Chinese children 11 . Using primary fibroblasts and osteoblasts from affected individuals, we recently demonstrated that absence of TRIC-B disrupts ER calcium flux kinetics, consistent with increased activation of the PERK/ATF4 pathway of ER stress 12 .…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect

Webb

Balasubramanian

Fratzl‐Zelman

et al. 2017

The Journal of Clinical Endocrinology &Amp; Metabolism

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ReuseUnless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. Disclosures: All authors state that they have no conflicts of interest. Takedown Supplemental data not included with this paper (see separate files)2 AbstractContext:Recessive mutations in TMEM38B cause type XIV osteogenesis imperfecta (OI; OMIM 611236) by dysregulating intracellular calcium flux. Objectives:Clinical and bone material phenotype description and osteoblast differentiation studies. Design and Setting:Natural history study in paediatric research centres.Patients:Eight patients with type XIV OI. Main Outcome Measures:Clinical examinations included; bone mineral density, radiographs, echocardiography and muscle biopsy. Bone biopsy samples (n=3) were analysed for histomorphometry and bone mineral density distribution by quantitative backscattered electron microscopy and Raman microspectroscopy. Cellular differentiation studies were performed on proband osteoblasts and normal murine osteoclasts. Results:The clinical phenotype of type XIV OI ranges from asymptomatic to severe. Previously unreported features include vertebral fractures, periosteal cloaking, coxa vara and extraskeletal features (muscular hypotonia, cardiac abnormalities). Proband L1-L4 bone density Z-score was reduced (median -3.3 [range -4.77 to +0.1; n=7]), and increased by +1.7 (1.17 to 3.0; n=3) following bisphosphonate therapy. TMEM38B mutant bone has reduced trabecular bone volume, osteoblast and particularly osteoclast numbers, with >80% reduction in bone resorption. Bone mineralization density is normal/slightly increased. We demonstrate a complex osteoblast differentiation defect with decreased 3 expression of early markers and increased late, mineralisation-related markers.Predominance of TRIC-B over TRIC-A expression in murine osteoclasts supports an intrinsic osteoclast defect underlying low bone turnover.Conclusions: OI type XIV has a bone histology, mineralization and osteoblast differentiation pattern that is distinct from type I OI. Probands are responsive to bisphosphonates but show muscular and cardiovascular features possibly related to intracellular calcium flux abnormalities.4

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Section: Molecular Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect

Webb

Balasubramanian

Fratzl‐Zelman

et al. 2017

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…1B, the Arabic mutant locus encodes a truncated TRIC-B protein lacking the carboxy-terminal half (mutation 1), 21,22) whereas the 5′-terminal region encompassing exons 1 and 2 is deleted in the Albanian mutant locus (mutation 2). 23) Furthermore, three additional loci were recently reported in Chinese and American OI patients 24,25) ; a mutation disrupting the acceptor splice site of intron 3 (mutation 3), and mutations in exon 4 (mutation 4) and exon 1 (mutation 5). These critical OI-causing mutations presumably result in functionally-defective TRIC-B channels.…”

Section: Osteogenesis Imperfecta (Oi)mentioning

confidence: 99%

“…These critical OI-causing mutations presumably result in functionally-defective TRIC-B channels. Based on the phenotypes of 22 cases reported to date, [21][22][23][24] OI patients bearing the TRIC-B mutations develop moderately severe OI, and have various fracture frequency, mildly or moderately short stature, gray to blue sclera and no tooth defect. However, the pathophysiological mechanism remains to be addressed in these OI patients.…”

Section: Osteogenesis Imperfecta (Oi)mentioning

confidence: 99%

“…Tric-b-knockout mice exhibit birth asphyxia due to poor surfactant production in alveolar epithelial cells, 12) while no respiratory failure was reported in the OI patients. [21][22][23][24] It is unclear why this phenotypical difference is observed. In mouse alveolar cells, Tric-a expression is very low, and TRIC-B channels might predominantly mediate counter-ionic currents during ER Ca 2+ release.…”

Section: Future Perspectivementioning

confidence: 99%

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TRIC-B Mutations Causing Osteogenesis Imperfecta

Ichimura

Takeshima

2016

Biological & Pharmaceutical Bulletin

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Trimeric intracellular cation (TRIC) channel subtypes, namely TRIC-A and TRIC-B, are expressed in the endoplasmic/sarcoplasmic reticulum and nuclear envelope, and likely function as monovalent cation channels in various cell types. Our studies using knockout mice so far suggest that TRIC subtypes support Ca 2 release from intracellular stores by mediating counter-cationic fluxes. Several genetic mutations within the TRIC-B locus were recently identified in autosomal recessive osteogenesis imperfecta (OI) patients. However, the molecular mechanism by which the mutations cause human disease is not fully addressed. We found that Tric-b-knockout mice exhibit poor bone ossification and thus serve as an OI-model animal. Studies on Tric-b-knockout bones and cultured cell lines derived from the patients currently reveal the main part of the pathophysiological mechanism involved in the TRIC-B-mutated OI form. This mini-review focuses on the essential role of TRIC-B channels in bone ossification.

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The molecular landscape of osteogenesis imperfecta in a Brazilian tertiary service cohort

et al. 2020

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A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta

Cited by 42 publications

References 7 publications

Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect

Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect

TRIC-B Mutations Causing Osteogenesis Imperfecta

The molecular landscape of osteogenesis imperfecta in a Brazilian tertiary service cohort

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