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