Abstract
A novel brachydactyly with duplication of proximal phalanges was discovered while traveling to the Lost City of Petra. By homozygosity mapping it was delineated 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 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 propose that CHSY1, a novel FRINGE enzyme, is essential for inhibition of NOTCH signaling during human embryonic development.
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