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

Celine Denais (1) , Carolyn Dent (1) , Laura Southgate (1) , Jacqueline Hoyle (1) , Dimitra Dafou (1) , Richard Charles Trembath (1) , Rajiv David Machado (2)

1 Medical and Molecular Genetics
2 Medical and molecular genetics

Dyggve-Melchior-Clausen syndrome (DMC), a severe autosomal recessive skeletal disorder with mental retardation, is caused by mutation of the gene encoding Dymeclin. 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 fibres. DMC cells have an elevated apoptotic index (p<0.01) likely due to a stress response contingent upon Golgi-related trafficking defects. We performed spatio-temporal 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.

Mots clés: Life Sciences

Celine Denais, Carolyn Dent, Laura Southgate, Jacqueline Hoyle, Dimitra Dafou, et al.. Dymeclin, the gene underlying Dyggve-Melchior-Clausen syndrome, encodes a protein integral to extracellular matrix and Golgi organisation and is associated with protein secretion pathways critical in bone development.. Human Mutation, 2011, 32 (2), pp.231. ⟨10.1002/humu.21413⟩. ⟨hal-00612011⟩