Dymeclin, the gene underlying Dyggve-Melchior-Clausen syndrome, encodes a protein integral to extracellular matrix and golgi organization and is associated with protein secretion pathways critical in bone development

Denais, Celine and Dent, Carolyn L. and Southgate, Laura and Hoyle, Jacqueline and Dafou, Dimitra and Trembath, Richard C. and Machado, Rajiv D. (2011) Dymeclin, the gene underlying Dyggve-Melchior-Clausen syndrome, encodes a protein integral to extracellular matrix and golgi organization and is associated with protein secretion pathways critical in bone development. Human mutation, 32 (2). pp. 231-239. ISSN 1059-7794

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Official URL: http://dx.doi.org/10.1002/humu.21413

Abstract

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.

Item Type:Article
Keywords:Dyggve-Melchior-Clausen syndrome, Dymeclin, Bone development
Subjects:C Biological Sciences > C141 Developmental Biology
C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
Divisions:College of Science > School of Life Sciences
ID Code:6313
Deposited By: Rajiv Machado
Deposited On:11 Oct 2012 06:17
Last Modified:29 Nov 2013 09:40

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