ZFIN ID: ZDB-PUB-101209-19
Loss of CHSY1, a Secreted FRINGE Enzyme, Causes Syndromic Brachydactyly in Humans via Increased NOTCH Signaling
Tian, 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., and Reversade, B.
Date: 2010
Source: American journal of human genetics   87(6): 768-778 (Journal)
Registered Authors: REVERSADE, Bruno, Tian, Jing
Keywords: none
MeSH Terms:
  • Amino Acid Sequence
  • Cells, Cultured
  • Female
  • Foot Deformities, Congenital/genetics*
  • Frameshift Mutation
  • Genotype
  • Hand Deformities, Congenital/genetics*
  • Humans
  • Male
  • Molecular Sequence Data
  • N-Acetylgalactosaminyltransferases/chemistry
  • N-Acetylgalactosaminyltransferases/genetics*
  • Pedigree
  • Polymerase Chain Reaction
  • RNA Interference
  • Receptors, Notch/metabolism*
  • Sequence Homology, Amino Acid
  • Signal Transduction*
  • Syndrome
PubMed: 21129727 Full text @ Am. J. Hum. Genet.
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.