Lazarus Syndia, McInerney-Leo Aideen M, McKenzie Fiona A, Baynam Gareth, Broley Stephanie, Cavan Barbra V, Munns Craig F, Pruijs Johannes Egbertus Hans, Sillence David, Terhal Paulien A, Pryce Karena, Brown Matthew A, Zankl Andreas, Thomas Gethin, Duncan Emma L
The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
BMC Musculoskelet Disord. 2014 Mar 27;15:107. doi: 10.1186/1471-2474-15-107.
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 sample 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. Individuals with identical mutations in IFITM5 have highly variable phenotypic expression, even within the same family.
导致Ⅴ型成骨不全症（OI）的基因突变最近被确定为IFITM5基因5'非翻译区（UTR）中的一个单点突变（c.-14C>T），IFITM5是一个编码跨膜蛋白的基因，其表达仅限于骨骼组织。该突变产生了一个替代起始密码子，并且在真核细胞系中已显示会导致IFITM5的一种更长的变体，但此前尚未在Ⅴ型OI患者的骨骼中证实其表达情况。
对我们临床诊断为Ⅴ型OI的受试者队列进行IFITM5基因5'UTR的桑格测序。从转诊的临床医生处收集临床数据。从一名患者的骨样本中提取RNA，并进行桑格测序以确定野生型和突变型IFITM5的表达情况。
所有9名Ⅴ型OI受试者均为c.-14C>T IFITM5突变的杂合子。临床上，表型存在异质性，尤其是在受试者的骨脆性表现方面。野生型和突变型IFITM5 mRNA转录本均存在于骨骼中。
c.-14C>T IFITM5突变不会导致RNA无效等位基因，但在骨骼中表达。即使在同一家族中，IFITM5具有相同突变的个体也具有高度可变的表型表达。
