Fitzgerald Jamie, Holden Paul, Wright Hollis, Wilmot Beth, Hata Abigail, Steiner Robert D, Basel Don
Department of Orthopaedics and Rehabilitation, Oregon Health & Science University (OHSU), Portland, Oregon.
Department of Molecular and Medical Genetics, OHSU.
J Rare Disord. 2013 Dec;1(2):37-42.
Osteogenesis imperfecta (OI) type V is a dominantly inherited skeletal dysplasia characterized by fractures and progressive deformity of long bones. In addition, patients often present with radial head dislocation, hyperplastic callus, and calcification of the forearm interosseous membrane. Recently, a specific mutation in the gene was found to be responsible for OI type V. This mutation, a C to T transition 14 nucleotides upstream from the endogenous start codon, creates a new start methionine that appears to be preferentially used by the translational machinery. However, the mechanism by which the lengthened protein results in a dominant type of OI is unknown.
We report 7 ethnically diverse (African-American, Caucasian, Hispanic, and African) individuals with OI type V from 2 families and 2 sporadic cases. Exome sequencing failed to identify a causative mutation. Using Sanger sequencing, we found that all affected individuals in our cohort possess the c.-14 variant, further supporting the notion that OI type V is caused by a single, discrete mutation. Our patient cohort demonstrated inter-and intrafamilial phenotypic variability, including a father with classic OI type V whose daughter had a phenotype similar to OI type I. This clinical variability suggests that modifier genes influence the OI type V phenotype. We also confirm that the mutation creates an aberrant IFITM5 protein containing an additional 5 amino acids at the N-terminus.
The variable clinical signs in these cases illustrate the significant variability of the OI type V phenotype caused by the c.-14 mutation. The affected individuals are more ethnically diverse than previously reported.
V型成骨不全症（OI）是一种常染色体显性遗传性骨骼发育不良，其特征为骨折和长骨进行性畸形。此外，患者常出现桡骨头脱位、骨痂增生以及前臂骨间膜钙化。最近，发现该基因中的一个特定突变是V型OI的病因。此突变是在内源起始密码子上游14个核苷酸处由C到T的转换，产生了一个新的起始甲硫氨酸，似乎被翻译机制优先使用。然而，延长的蛋白质导致显性OI类型的机制尚不清楚。
我们报告了来自2个家庭的7名不同种族（非裔美国人、白种人、西班牙裔和非洲人）的V型OI患者以及2例散发病例。外显子组测序未能鉴定出致病突变。使用桑格测序法，我们发现我们队列中的所有受影响个体都具有c.-14变异，进一步支持了V型OI是由单个离散突变引起的观点。我们的患者队列表现出家族间和家族内的表型变异性，包括一位患有典型V型OI的父亲，其女儿具有类似于I型OI的表型。这种临床变异性表明修饰基因影响V型OI表型。我们还证实该突变产生了一种异常的IFITM5蛋白，其N端额外含有5个氨基酸。
这些病例中可变的临床体征说明了由c.-14突变引起的V型OI表型的显著变异性。受影响个体的种族比先前报道的更多样化。
