Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by<i>TMEM38B</i>mutation

Shaheen, Ranad; Alazami, Anas M.; Alshammari, Muneera; Faqeih, Eissa; Al‐Hashmi, Nadia; Mousa, Noon; Al-Sinani, Aisha; Ansari, Shinu; Alzahrani, Fatema; Al‐Owain, Mohammed; Al-Zayed, Zayed; Alkuraya, Fowzan S.

doi:10.1136/jmedgenet-2012-101142

Cited by 132 publications

(101 citation statements)

References 25 publications

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“…[1][2][3][4][5][6][7][8][9][10][11][12][13] On the contrary, here 15/32 families with no mutation in collagen I had a typical type I phenotype, and 25 additional families were excluded on the basis of a negative sequencing result in combination with an unclear clinical phenotype. These individuals may have a COL1A1 null allele caused by a non-exonic mutation missed here; however, another OI-related gene might be causative in some instances.…”

Section: Noteworthy Mutationsmentioning

confidence: 99%

“…Dominant mutations in collagen type I are generally stated to be responsible for 90% of cases, while a plethora of other genes have been associated with non-collagen OI in recent years. [1][2][3][4][5][6][7][8][9][10][11][12][13] Collagen type I, encoded by COL1A1 and COL1A2, constitutes 85% of the organic matrix in skeletal tissue, and forms a framework for mineral deposition, rendering bone the tensile properties needed to withstand torsion and bending powers. Procollagen is a heterotrimer, with a helical 1014-amino acid-long central stretch of two α1-and one α2-chains, which is flanked by globular N-and C-terminal regions.…”

Section: Introductionmentioning

confidence: 99%

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Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

et al. 2015

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Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype-phenotype studies on 4100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the α1-and α2-chains were associated with the absence of dentinogenesis imperfecta (Po0.0001 vs 0.0049), while only those in the α1-chain were associated with blue sclera (P = 0.0110). Comparing glycine with serine substitutions, α1-alterations were associated with more severe phenotype (P = 0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (Po0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent 495% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in 495% of an entire OI population.

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Section: Noteworthy Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

et al. 2015

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“…Furthermore, the success we have had in combining autozygome and exome analysis in delineating the genetic architecture of other genetically heterogeneous disorders, for example, Osteogenesis imperfecta, retinal dystrophy, cataract, mitochondrial diseases, Bardet-Biedl syndrome, and Joubert syndrome 26,[28][29][30][31] 33 ), encouraged us to use a similar approach on MKS to not only determine the mutation distribution in known MKS disease genes but to also potentially identify novel candidate disease genes.…”

Section: Discussionmentioning

confidence: 99%

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

et al. 2012

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Meckel-Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n ¼ 12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis-van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.

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“…As shown in Fig. 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).…”

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 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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Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined byTMEM38Bmutation

Abstract: TMEM38B is a novel candidate gene for AR OI. Future studies are needed to explore fully the contribution of this gene to AR OI in other populations.

Cited by 132 publications

References 25 publications

Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

TRIC-B Mutations Causing Osteogenesis Imperfecta

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