期刊
HUMAN MUTATION
卷 32, 期 2, 页码 231-239出版社
WILEY
DOI: 10.1002/humu.21413
关键词
Dymeclin; Skeletal dysplasia; secretion; chondrogenesis; Golgi
资金
- British Heart Foundation [RG/08/006/25302, FS/07/036, FS/06/051]
- Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre
- British Heart Foundation [RG/08/006/25302] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10379] Funding Source: researchfish
Dyggve-Melchior-Clausen syndrome (DMC), a severe autosomal recessive skeletal disorder with mental retardation, is caused by mutation of the gene encoding Dymeclin (DYM). Employing patient fibroblasts with mutations characterized at the genomic and, for the first time, transcript level, we identified profound disruption of Golgi organization as a pathogenic feature, resolved by transfection of heterologous wild-type Dymeclin. Collagen targeting appeared defective in DMC cells leading to near complete absence of cell surface collagen fibers. DMC cells have an elevated apoptotic index (P < 0.01) likely due to a stress response contingent upon Golgi-related trafficking defects. We performed spatiotemporal mapping of Dymeclin expression in zebrafish embryos and identified high levels of transcript in brain and cartilage during early development. Finally, in a chondrocyte cDNA library, we identified two novel secretion pathway proteins as Dymeclin interacting partners: GOLM1 and PPIB. Together these data identify the role of Dymeclin in secretory pathways essential to endochondral bone formation during early development. Hum Mutat 32:231-239, 2011. (C) 2011 Wiley-Liss, Inc.
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