P97. Loss of CHSY1, a novel FRINGE enzyme, causes syndromic brachydactyly via increased NOTCH signaling

We delineated a novel syndromic brachydactyly with partial duplication of proximal phalanges to 16.8 Mb over 4 chromosomes. High-throughput sequencing of all 177 candidate genes detected a disease-causing frameshift mutation in the gene CHSY1 encoding for a chondroitin synthase with a Fringe motif....

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Bibliographic Details
Published in:Differentiation (London) 2010-11, Vol.80, p.S49-S50
Main Authors: Tian, A.J., Ling, L., Shboul, M., Lee, H., O'Connor, B., Merriman, B., Nelson, S.F., Cool, S., Ababneh, O.H., Al-Hadidy, A., Masri, A., Hamamy, H., Reversade, B.
Format: Article
Language:English
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Summary:We delineated a novel syndromic brachydactyly with partial duplication of proximal phalanges to 16.8 Mb over 4 chromosomes. High-throughput sequencing of all 177 candidate genes detected a disease-causing frameshift mutation in the gene CHSY1 encoding for a chondroitin synthase with a Fringe motif. CHSY1 was secreted from patient's fibroblasts where its absence triggered remarkable JAG1 synthesis and NOTCH up-regulation. Chsy1-knockdown in zebrafish embryos partially phenocopies the human disorder: increasing NOTCH output, impairing pectoral fin development and leading to dramatic retinal overgrowth. We conclude that CHSY1 is a novel FRINGE enzyme necessary to restrict NOTCH signaling during various developmental processes.
ISSN:0301-4681
1432-0436
DOI:10.1016/j.diff.2010.09.103