title: A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V.
abstract: 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.
authors.affiliation: Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul 110-744, Republic of Korea. tjcho@snu.ac.kr
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cho
authors.forename: Kyung-Eun
authors.initials: KE
authors.lastname: Lee
authors.forename: Sook-Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Su Jeong
authors.initials: SJ
authors.lastname: Song
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Kim
authors.forename: Daehyun
authors.initials: D
authors.lastname: Jeon
authors.forename: Gene
authors.initials: G
authors.lastname: Lee
authors.forename: Ha-Neui
authors.initials: HN
authors.lastname: Kim
authors.forename: Hye Ran
authors.initials: HR
authors.lastname: Lee
authors.forename: Hye-Hyun
authors.initials: HH
authors.lastname: Eom
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.forename: Ok-Hwa
authors.initials: OH
authors.lastname: Kim
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.forename: Sung Sup
authors.initials: SS
authors.lastname: Park
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Won Joon
authors.initials: WJ
authors.lastname: Yoo
authors.forename: In Ho
authors.initials: IH
authors.lastname: Choi
authors.forename: Jung-Wook
authors.initials: JW
authors.lastname: Kim
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D011859:Radiography; D017422:Sequence Analysis, DNA
chemical_list: D020121:5' Untranslated Regions; C575746:IFITM5 protein, human; D008565:Membrane Proteins