The gene responsible for Dyggve-Melchior-Clausen syndrome encodes a novel peripheral membrane protein dynamically associated with the Golgi apparatus

Ariane Dimitrov, Vincent Paupe, Charles Gueudry, Jean-Baptiste Sibarita, Graça Raposo, Ole Vielemeyer, Thierry Gilbert, Zsolt Csaba, Tania Attie-Bitach, Valérie Cormier-Daire, Pierre Gressens, Pierre Rustin, Franck Perez, Vincent El Ghouzzi
Human Molecular Genetics. 2008-11-07; 18(3): 440-453
DOI: 10.1093/hmg/ddn371

Dimitrov A(1), Paupe V, Gueudry C, Sibarita JB, Raposo G, Vielemeyer O, Gilbert
T, Csaba Z, Attie-Bitach T, Cormier-Daire V, Gressens P, Rustin P, Perez F, El
Ghouzzi V.

Author information:
(1)UMR CNRS 144, Institut Curie, 75005 Paris, France.

Erratum in
Hum Mol Genet. 2009 May 1;18(9):1714-6.

Dyggve-Melchior-Clausen dysplasia (DMC) is a rare inherited dwarfism with severe
mental retardation due to mutations in the DYM gene which encodes Dymeclin, a
669-amino acid protein of yet unknown function. Despite a high conservation
across species and several predicted transmembrane domains, Dymeclin could not
be ascribed to any family of proteins. Here we show, using in situ
hybridization, that DYM is widely expressed in human embryos, especially in the
cortex, the hippocampus and the cerebellum. Both the endogenous and the
recombinant protein fused to green fluorescent protein co-localized with Golgi
apparatus markers. Electron microscopy revealed that Dymeclin associates with
the Golgi apparatus and with transitional vesicles of the reticulum-Golgi
interface. Moreover, permeabilization assays revealed that Dymeclin is not a
transmembrane but a peripheral protein of the Golgi apparatus as it can be
completely released from the Golgi after permeabilization of the plasma
membrane. Time lapse confocal microscopy experiments on living cells further
showed that the protein shuttles between the cytosol and the Golgi apparatus in
a highly dynamic manner and recognizes specifically a subset of mature Golgi
membranes. Finally, we found that DYM mutations associated with DMC result in
mis-localization and subsequent degradation of Dymeclin. These data indicate
that DMC results from a loss-of-function of Dymeclin, a novel peripheral
membrane protein which shuttles rapidly between the cytosol and mature Golgi
membranes and point out a role of Dymeclin in cellular trafficking.