Affordable Access

deepdyve-link
Publisher Website

Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling.

Authors
  • J, Tian
  • L, Ling
  • M, Shboul
  • Hane Lee
  • B, O Connor
  • B, Merriman
  • Stanley F. Nelson
  • S, Cool
  • Oh, Ababneh
  • A, Al-Hadidy
  • A, Masri
  • H, Hamamy
  • B, Reversade
Type
Published Article
Journal
The American Journal of Human Genetics
Publisher
Elsevier
Volume
87
Issue
6
Pages
768–778
Identifiers
DOI: 10.1016/j.ajhg.2010.11.005
Source
Nelson Lab
License
Unknown

Abstract

We delineated a syndromic recessive preaxial brachydactyly with partial duplication of proximal phalanges to 16.8 Mb over 4 chromosomes. High-throughput sequencing of all 177 candidate genes detected a truncating frameshift mutation in the gene CHSY1 encoding a chondroitin synthase with a Fringe domain. CHSY1 was secreted from patients fibroblasts and was required for synthesis of chondroitin sulfate moieties. Noticeably, its absence triggered massive production of JAG1 and subsequent NOTCH activation, which could only be reversed with a wild-type but not a Fringe catalytically dead CHSY1 construct. In vitro, depletion of CHSY1 by RNAi knockdown resulted in enhanced osteogenesis in fetal osteoblasts and remarkable upregulation of JAG2 in glioblastoma cells. In vivo, chsy1 knockdown in zebrafish embryos partially phenocopied the human disorder; it increased NOTCH output and impaired skeletal, pectoral-fin, and retinal development. We conclude that CHSY1 is a secreted FRINGE enzyme required for adjustment of NOTCH signaling throughout human and fish embryogenesis and particularly during limb patterning.

Report this publication

Statistics

Seen <100 times