A Single Recurrent Mutation in the 5′-UTR of IFITM5 Causes Osteogenesis Imperfecta Type V

• DOI: 10.1016/j.ajhg.2012.06.005
• Publication Date: 2012-08-02T15:49:51Z
• Authors: Tae-Joon Cho; Kyung-Eun Lee; Sook-Kyung Lee; Su Jeong Song; Kyung Jin Kim; Daehyun Jeon; Gene Lee; Ha-Neui Kim; Hye Ran Lee; Hye-Hyun Eom; Zang Hee Lee; Ok-Hwa Kim; Woong-Yang Park; Sung Sup Park; Shiro Ikegawa; Won Joon Yoo; In Ho Choi; Jung-Wook Kim
• Keywords: Adult; Male; 0303 health sciences; Adolescent; Base Sequence; Genetic Linkage; Molecular Sequence Data; Membrane Proteins; Sequence Analysis, DNA; Osteogenesis Imperfecta; Radiography; 03 medical and health sciences; Genetics; Humans; Point Mutation; Genetics(clinical); Exome; Female; Amino Acid Sequence; 5' Untranslated Regions; Child

Osteogenesis imperfecta (OI) is a heterogenous group of genetic disorders of bone fragility. OI type V is an autosomal-dominant disease characterized by calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation; the causative mutation involved in this disease has not been discovered yet. Using linkage analysis in a four-generation family and whole-exome sequencing, we identified a heterozygous mutation of c.-14C>T in the 5'-untranslated region of a gene encoding interferon-induced transmembrane protein 5 (IFITM5). It completely cosegregated with the disease in three families and occurred de novo in five simplex individuals. Transfection of wild-type and mutant IFITM5 constructs revealed that the mutation added five amino acids (Met-Ala-Leu-Glu-Pro) to the N terminus of IFITM5. Given that IFITM5 expression and protein localization is restricted to the skeletal tissue and IFITM5 involvement in bone formation, we conclude that this recurrent mutation would have a specific effect on IFITM5 function and thus cause OI type V.