Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia

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 “leontiasi...

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Published in:Human genetics 2011-05, Vol.129 (5), p.497-502
Main Authors: Kim, Su Jin, Bieganski, Tadeusz, Sohn, Young Bae, Kozlowski, Kazimierz, Semënov, Mikhail, Okamoto, Nobuhiko, Kim, Chi Hwa, Ko, Ah-Ra, Ahn, Geung Hwan, Choi, Yoon-La, Park, Sung Won, Ki, Chang-Seok, Kim, Ok-Hwa, Nishimura, Gen, Unger, Sheila, Superti-Furga, Andrea, Jin, Dong-Kyu
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - genetics
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Bone Morphogenetic Proteins - genetics
Child
Classical genetics, quantitative genetics, hybrids
Cloning
Craniofacial Abnormalities - genetics
Diseases of the osteoarticular system
Dysplasia
Female
Fundamental and applied biological sciences. Psychology
Gene Function
Genetic aspects
Genetic Markers - genetics
Genetics of eukaryotes. Biological and molecular evolution
Hospitals
Human
Human Genetics
Humans
Male
Malformations and congenital and or hereditary diseases involving bones. Joint deformations
Maternal & child health
Medical sciences
Medicine
Metabolic Diseases
Molecular Medicine
Mutagenesis
Mutation
Original Investigation
Osteochondrodysplasias
Patients
Pediatrics
Peptides
Protein Interaction Domains and Motifs - genetics
Protein Sorting Signals - genetics
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Summary: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.
ISSN:0340-6717
1432-1203
DOI:10.1007/s00439-011-0947-3