期刊
PLOS ONE
卷 12, 期 12, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0189591
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资金
- Swedish Research Council [K-2013-52X-22198-01-3]
- Stockholm County Council
- Karolinska Institutet
- Department of Research and Development of Vasternorrland County Council
- Karolinska Institutet research funds
- Research and Development Council of Region Skke
- Swedish Society of Spinal Surgeons
- Visare Norr fund from the Northern County Councils Regional Federation
- Scoliosis Research Society
- Alfred Osterlund Foundation
- Emil Andersson Foundation
- Royal Society Wolfson Research Excellence Award
- NIH [P01 HD084387]
A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c. G6859A change in exon 21 (NM_001408), leading to a predicted p. V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.
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