Abstract:Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal-dominant inheritance, but many autosomal-recessive genes have been reported. We applied whole-exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a… Show more
“…We identified three novel homozygous BMP1 missense variants affecting highly conserved amino acids located in the catalytic metalloprotease domain, which may thus interfere with the enzymatic activity of the BMP1/tolloidlike protein. Hitherto, four BMP1 missense variants have been reported (Asharani et al 2012;Martinez-Glez et al 2012;Valencia et al 2014;Cho et al 2015;Syx et al 2015). Two of them, c.747C>G p.(Phe249Leu) and c.808A>G p. (Met270Val), are in the same domain as the variants we identified (Fig.…”
Section: Discussionsupporting
confidence: 62%
“…; Cho et al. ). The phenotypes of those two patients were severe in accordance with the phenotype of our patient harboring the c.818C>T p.(Ala273Val) variant.…”
BackgroundOsteogenesis imperfecta (OI) is a heterogeneous hereditary connective tissue disorder clinically hallmarked by increased susceptibility to bone fractures.MethodsWe analyzed a cohort of 77 diagnosed OI patients from 49 unrelated Palestinian families. Next‐generation sequencing technology was used to screen a panel of known OI genes.ResultsIn 41 probands, we identified 28 different disease‐causing variants of 9 different known OI genes. Eleven of the variants are novel. Ten of the 28 variants are located in COL1A1, five in COL1A2, three in BMP1, three in FKBP10, two in TMEM38B, two in P3H1, and one each in CRTAP,SERPINF1, and SERPINH1. The absence of disease‐causing variants in the remaining eight probands suggests further genetic heterogeneity in OI. In general, most OI patients (90%) harbor mainly variants in type I collagen resulting in an autosomal dominant inheritance pattern. However, in our cohort almost 61% (25/41) were affected with autosomal recessive OI. Moreover, we document a 21‐kb genomic deletion in the TMEM38B gene identified in 29% (12/41) of the tested probands, making it the most frequent OI‐causing variant in the Palestinian population.ConclusionThis is the first genetic screening of an OI cohort from the Palestinian population. Our data are important for genetic counseling of OI patients and families in highly consanguineous populations.
“…We identified three novel homozygous BMP1 missense variants affecting highly conserved amino acids located in the catalytic metalloprotease domain, which may thus interfere with the enzymatic activity of the BMP1/tolloidlike protein. Hitherto, four BMP1 missense variants have been reported (Asharani et al 2012;Martinez-Glez et al 2012;Valencia et al 2014;Cho et al 2015;Syx et al 2015). Two of them, c.747C>G p.(Phe249Leu) and c.808A>G p. (Met270Val), are in the same domain as the variants we identified (Fig.…”
Section: Discussionsupporting
confidence: 62%
“…; Cho et al. ). The phenotypes of those two patients were severe in accordance with the phenotype of our patient harboring the c.818C>T p.(Ala273Val) variant.…”
BackgroundOsteogenesis imperfecta (OI) is a heterogeneous hereditary connective tissue disorder clinically hallmarked by increased susceptibility to bone fractures.MethodsWe analyzed a cohort of 77 diagnosed OI patients from 49 unrelated Palestinian families. Next‐generation sequencing technology was used to screen a panel of known OI genes.ResultsIn 41 probands, we identified 28 different disease‐causing variants of 9 different known OI genes. Eleven of the variants are novel. Ten of the 28 variants are located in COL1A1, five in COL1A2, three in BMP1, three in FKBP10, two in TMEM38B, two in P3H1, and one each in CRTAP,SERPINF1, and SERPINH1. The absence of disease‐causing variants in the remaining eight probands suggests further genetic heterogeneity in OI. In general, most OI patients (90%) harbor mainly variants in type I collagen resulting in an autosomal dominant inheritance pattern. However, in our cohort almost 61% (25/41) were affected with autosomal recessive OI. Moreover, we document a 21‐kb genomic deletion in the TMEM38B gene identified in 29% (12/41) of the tested probands, making it the most frequent OI‐causing variant in the Palestinian population.ConclusionThis is the first genetic screening of an OI cohort from the Palestinian population. Our data are important for genetic counseling of OI patients and families in highly consanguineous populations.
“…Asharani and colleagues found detectable plasma P1CP at levels just below the normal range in two patients with mutations that affected the signal peptide of BMP1, which confirmed that cleavage of the C‐propeptide occurred, suggesting that alternate enzymes facilitated the event. To date, 18 people with OI due to BMP1 mutations have been described . They share some phenotypic features with those with substrate alterations—white sclerae and absence of dentinogenesis imperfecta—but their fracture phenotype is more severe: 28% had fractures in utero or at birth and 85% had fractured by the age of 2 years.…”
Osteogenesis imperfecta (OI) is a genetic bone disorder characterized by fractures, low bone mass, and skeletal fragility. It most commonly arises from dominantly inherited mutations in the genes COL1A1 and COL1A2 that encode the chains of type I collagen. A number of recent reports have suggested that mutations affecting the carboxyl-terminal propeptide cleavage site in the products of either COL1A1 or COL1A2 give rise to a form of OI characterized by unusually dense bones. We have assembled clinical, biochemical, and molecular data from 29 individuals from 8 families with 7 different mutations affecting the C-propeptide cleavage site. The phenotype was generally mild: The median height was ~33th centile. Eighty percent of subjects had their first fracture by the age of 10 years, and one-third had a femoral or tibial fracture by the age of 25 years. Fractures continued into adulthood, though rates varied considerably. Healing was normal and rarely resulted in long bone deformity. One-third of subjects older than 15 years had scoliosis. The teeth and hearing were normal in most, and blue sclerae were not observed. Other features noted included fibro-osseous dysplasia of the mandible and Achilles tendon calcification. The mean spinal bone mineral density Z-score was +2.9 (SD 2.1) compared with −2.2 (0.7) in subjects with COL1A1 haploinsufficiency mutations. Bone mineral density distribution, assessed by quantitative backscattered electron imaging in bone showed higher levels of mineralization than found in any other disorder. Bone histology showed high trabecular volume and increased cortical thickness, with hyperosteoidosis and delayed mineralization. In vitro studies with cultured skin fibroblasts suggested that these mutations interfere with processing of the chain in which the sequence alteration occurs, but the C-propeptide is eventually cleaved (and detectable in blood), suggesting there are alternative sites of cleavage. The precise mechanism of the bony pathology is not yet clear.
“…*241 T > C; c.2107G > C (p.Glu703Gln)81Heterozygousc. 808A > G (p.Met270Val); c.1297G > T *
[16]91Heterozygousc.925delG (p.Asp309Thrfs*54); c.1492G > A (p.Gly498Arg)[11]101Heterozygousc.34G > C (p.Gly12Arg); c.1839delC (p.Asn614Thrfs*188)112Heterozygousc.34G > C (p.Gly12Arg); c.2188dupC (p.Gln730Profs*294)121Heterozygousc.796_797delTT (p.Phe266Argfs*25); c.2108-2A > GThis report*This variant caused exon 10 skippingFig. 3Map of the mutations in BMP1 and mTLD.…”
BackgroundOsteogenesis imperfecta (OI) is a collagen-related bone dysplasia leading to a susceptibility to fractures. OI can be caused by mutations in several genes including BMP1. It encodes two isoforms, bone morphogenetic protein 1 (BMP1) and mammalian tolloid (mTLD); both have proteolytic activity to remove the C-propeptide from procollagen.Case presentationWe report a Thai OI patient who had his first fracture at the age of three months. Using next generation sequencing, we successfully identified two novel compound heterozygous BMP1 mutations. One mutation, c.796_797delTT (p.Phe266Argfs*25) affects both BMP1 and mTLD isoforms, while the other, c.2108-2A > G, affects only the BMP1 isoform. Preservation of the mTLD may explain the relatively less severe clinical phenotype in this patient. Intravenous bisphosphonate was given from the age of 8 months to 5 years. He was free from fractures for 9 months before discontinuation.ConclusionThis case expands the mutation spectrum of BMP1, strengthens the correlation between genotype and phenotype, and supports the benefits of bisphosphonate in OI patients with BMP1 mutations.
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