title: 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.
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.
authors.affiliation: King's College London, Department of Medical & Molecular Genetics, School of Medicine, Guy's Hospital, London, United Kingdom.
authors.forename: Celine
authors.initials: C
authors.lastname: Denais
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Dent
authors.forename: Laura
authors.initials: L
authors.lastname: Southgate
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hoyle
authors.forename: Dimitra
authors.initials: D
authors.lastname: Dafou
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Rajiv D
authors.initials: RD
authors.lastname: Machado
mesh_terms: D000818:Animals; D001846:Bone Development; D002478:Cells, Cultured; D020219:Chondrogenesis; D003593:Cytoplasm / Q000378:metabolism; D004392:Dwarfism / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008607:Intellectual Disability / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D010009:Osteochondrodysplasias / Q000151:congenital / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D012867:Skin / Q000166:cytology; D020798:Two-Hybrid System Techniques; D015027:Zebrafish / Q000196:embryology
chemical_list: C477370:DYM protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins