Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation.

Lang MR, Lapierre LA, Frotscher M, Goldenring JR, Knapik EW
Nat Genet. 2006 38 (10): 1198-203

PMID: 16980978 · DOI:10.1038/ng1880

An increasing number of human disorders have been linked to mutations in genes of the secretory pathway. The chemically induced zebrafish crusher variant results in malformed craniofacial skeleton, kinked pectoral fins and a short body length. By positional cloning, we identified a nonsense mutation converting leucine to a stop codon (L402X) in the sec23a gene, an integral component of the COPII complex, which is critical for anterograde protein trafficking between endoplasmic reticulum and Golgi apparatus. Zebrafish crusher mutants develop normally until the onset of craniofacial chondrogenesis. crusher chondrocytes accumulate proteins in a distended endoplasmic reticulum, resulting in severe reduction of cartilage extracellular matrix (ECM) deposits, including type II collagen. We demonstrate that the paralogous gene sec23b is also an essential component of the ECM secretory pathway in chondrocytes. In contrast, knockdown of the COPI complex does not hinder craniofacial morphogenesis. As SEC23A lesions cause the cranio-lenticulo-sutural dysplasia syndrome, crusher provides the first vertebrate model system that links the biology of endoplasmic reticulum to Golgi trafficking with a clinically relevant dysmorphology.

MeSH Terms (18)

Animals Cartilage Chondrocytes Collagen COP-Coated Vesicles Embryo, Nonmammalian Endoplasmic Reticulum Extracellular Matrix Facial Bones Gene Expression Regulation, Developmental Genetic Linkage Golgi Apparatus Mutation Protein Structure, Tertiary Protein Transport Vesicular Transport Proteins Zebrafish Zebrafish Proteins

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