Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation.
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.
Lang
Michael R
MR
Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Lapierre
Lynne A
LA
Frotscher
Michael
M
Goldenring
James R
JR
Knapik
Ela W
EW
D000818:Animals; D022181:COP-Coated Vesicles / Q000378:metabolism; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D019902:Chondrocytes / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D004625:Embryo, Nonmammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005147:Facial Bones / Q000002:abnormalities*; D018507:Gene Expression Regulation, Developmental; D008040:Genetic Linkage; D006056:Golgi Apparatus / Q000378:metabolism; D009154:Mutation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
C512739:SEC23A protein, human; C514984:Sec23a protein, zebrafish; D033921:Vesicular Transport Proteins; D029961:Zebrafish Proteins; D003094:Collagen