Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia |
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Authors: | Su Jin Kim Tadeusz Bieganski Young Bae Sohn Kazimierz Kozlowski Mikhail Sem?nov Nobuhiko Okamoto Chi Hwa Kim Ah-Ra Ko Geung Hwan Ahn Yoon-La Choi Sung Won Park Chang-Seok Ki Ok-Hwa Kim Gen Nishimura Sheila Unger Andrea Superti-Furga Dong-Kyu Jin |
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Affiliation: | Center for Pediatric Oncology, National Cancer Center, Goyang, Korea. |
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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. |
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