title: Mutations in a novel gene Dymeclin (FLJ20071) are responsible for Dyggve-Melchior-Clausen syndrome.
abstract: Dyggve-Melchior-Clausen syndrome (DMC) is a rare autosomal-recessive disorder, the gene for which maps to chromosome 18q21.1. DMC is characterized by the association of a spondylo-epi-metaphyseal dysplasia and mental retardation. Electron microscopic study of cutaneous cells of an affected child showed dilated rough endoplasmic reticulum, enlarged and aberrant vacuoles and numerous vesicles. As the etiology of the disorder is unknown, we have used a positional cloning strategy to identify the DMC gene. We detected seven deleterious mutations within a gene predicted from a human transcript (FLJ20071) in 10 DMC families. The mutations were nonsense mutations (R194X, R204X, L219X, Q483X), splice site or frameshift mutations (K626N+92aa to stop). The DMC gene transcript is widely distributed but appears abundant in chondrocytes and fetal brain. The predicted protein product of the DMC gene yields little insight into its likely function, showing no significant homology to any known protein family. However, the carboxy terminal end comprises a cluster of dileucine motifs, highly conserved across species. We conclude that DMC syndrome is consequent upon loss of function of a gene that we propose to name Dymeclin, which may have a role in process of intracellular digestion of proteins.
authors.affiliation: Department of Medical Genetics and INSERM U393, Hôpital Necker Enfants Malades, 75015 Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: El Ghouzzi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dagoneau
authors.forename: Esther
authors.initials: E
authors.lastname: Kinning
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Wassim
authors.initials: W
authors.lastname: Chemaitilly
authors.forename: Catherine
authors.initials: C
authors.lastname: Prost-Squarcioni
authors.forename: Lihadh I
authors.initials: LI
authors.lastname: Al-Gazali
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012867:Skin / Q000473:pathology / Q000648:ultrastructure
chemical_list: C477370:DYM protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins