TY - JOUR
T1 - Mutations in a novel gene Dymeclin (FLJ20071) are responsible fo Dyggve-Melchior-Clausen syndrome
AU - El Ghouzzi, Vincent
AU - Dagoneau, Nathalie
AU - Kinning, Esther
AU - Thauvin-Robinet, Christel
AU - Chemaitilly, Wassim
AU - Prost-Squarcioni, Catherine
AU - Al-Gazali, Lihadh I.
AU - Verloes, Alain
AU - Le Merrer, Martine
AU - Munnich, Arnold
AU - Trembath, Richard C.
AU - Cormier-Daire, Valérie
N1 - Funding Information:
We thank Dr Laurence Colleaux for her help and advice. We also wish to thank Drs André Megarbané, Odile Boute, Aziz Sefiani and Smaïl Hadj-Rabia for their clinical assistance. We acknowledge Jean-Paul Monnet for technical assistance for electron microscopy, Noman Kadhom for the cell cultures and Laura Baumber for help with genotyping. Financial support from the Wellcome Trust (R.C.T.) is gratefully acknowledged.
PY - 2003/2/1
Y1 - 2003/2/1
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddg029
DO - 10.1093/hmg/ddg029
M3 - Article
C2 - 12554689
AN - SCOPUS:0037322729
SN - 0964-6906
VL - 12
SP - 357
EP - 364
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 3
ER -