title: Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia.
abstract: Sclerosteosis and Van Buchem disease are related recessive sclerosing bone dysplasias caused by alterations in the SOST gene. We tested the hypothesis that craniodiaphyseal dysplasia (CDD) (MIM 122860), an extremely rare sclerosing bone dysplasia resulting facial distortion referred to as "leontiasis ossea", could also be caused by SOST mutations. We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD. As these mutations are located in the secretion signal of the SOST gene, we tested their effect on secretion by transfecting the mutant constructs into 293E cells. Intriguingly, these mutations greatly reduced the secretion of SOST. We conclude that CDD, the most severe form of sclerotic bone disease, is part of a spectrum of disease caused by mutations in SOST. Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits seem to be caused by a dominant negative mechanism.
authors.affiliation: Center for Pediatric Oncology, National Cancer Center, Goyang, Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Bieganski
authors.forename: Young Bae
authors.initials: YB
authors.lastname: Sohn
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Kozlowski
authors.forename: Mikhail
authors.initials: M
authors.lastname: Semënov
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.forename: Chi Hwa
authors.initials: CH
authors.lastname: Kim
authors.forename: Ah-Ra
authors.initials: AR
authors.lastname: Ko
authors.forename: Geung Hwan
authors.initials: GH
authors.lastname: Ahn
authors.forename: Yoon-La
authors.initials: YL
authors.lastname: Choi
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Park
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Ki
authors.forename: Ok-Hwa
authors.initials: OH
authors.lastname: Kim
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Dong-Kyu
authors.initials: DK
authors.lastname: Jin
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002648:Child; D019465:Craniofacial Abnormalities / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D021382:Protein Sorting Signals / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D021382:Protein Sorting Signals; C422903:SOST protein, human