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CELSR2 is a candidate susceptibility gene in idiopathic scoliosis.

CELSR2 is a candidate susceptibility gene in idiopathic scoliosis.
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Einarsdottir E, Grauers A, Wang J, Jiao H, Escher SA, Danielsson A, Simony A, Andersen M, Christensen SB, Åkesson K, Kou I, Khanshour AM, Ohlin A, Wise C, Ikegawa S, Kere J, Gerdhem P,


Einarsdottir E, Grauers A, Wang J, Jiao H, Escher SA, Danielsson A, Simony A, Andersen M, Christensen SB, Åkesson K, Kou I, Khanshour AM, Ohlin A, Wise C, Ikegawa S, Kere J, Gerdhem P, (click to view)

Einarsdottir E, Grauers A, Wang J, Jiao H, Escher SA, Danielsson A, Simony A, Andersen M, Christensen SB, Åkesson K, Kou I, Khanshour AM, Ohlin A, Wise C, Ikegawa S, Kere J, Gerdhem P,

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PloS one 2017 12 1412(12) e0189591 doi 10.1371/journal.pone.0189591
Abstract

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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