👤 Catherine Prost-Squarcioni

Spondyloepimetaphyseal dysplasias (SEMD) represent a heterogeneous group of conditions composed of at least 15 well-defined entities. The classification is based on clinical, radiological and molecular findings. Among them, several conditions also include a mental retardation (MR) syndrome, namely Wolcott-Rallison syndrome, Dyggve-Melchior-Clausen syndrome (DMC) and lysosomal storage disorders. Here, we report on a novel form of SEMD with MR in two Pakistani sisters born to first-cousin parents. SEMD, MR, microcephaly, ataxia, facial dysmorphism and hirsutism of back and legs were noted in the two children. Skeletal findings included flat vertebral bodies with irregular vertebral plates, irregular and flared metaphyses with vertical striations, small and irregular epiphyses, small carpal bones and narrow iliac wings without lacy pelvis iliac crest. Similarities with DMC prompted us to test and eventually exclude the DMC gene, dymeclin, by direct sequencing. Similarly, we excluded the PAPSS2 gene (3'-alpha phosphoadenosine 5'-phosphosulphate synthase 2) responsible for SEMD Pakistani type. The combination of features observed in the two sisters does not fit with any previously reported SEMD and represents therefore a novel form of autosomal recessive SEMD with MR. Show less

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. Show less