👤 Pierre Gressens

Dymeclin is a Golgi-associated protein whose deficiency causes Dyggve-Melchior-Clausen syndrome (DMC, MIM #223800), a rare recessively inherited spondyloepimetaphyseal dysplasia consistently associated with postnatal microcephaly and intellectual disability. While the skeletal phenotype of DMC patients has been extensively described, very little is known about their cerebral anomalies, which result in brain growth defects and cognitive dysfunction. We used Dymeclin-deficient mice to determine the cause of microcephaly and to identify defective mechanisms at the cellular level. Brain weight and volume were reduced in all mutant mice from postnatal day 5 onward. Mutant mice displayed a narrowing of the frontal cortex, although cortical layers were normally organized. Interestingly, the corpus callosum was markedly thinner, a characteristic we also identified in DMC patients. Consistent with this, the myelin sheath was thinner, less compact and not properly rolled, while the number of mature oligodendrocytes and their ability to produce myelin basic protein were significantly decreased. Finally, cortical neurons from mutant mice and primary fibroblasts from DMC patients displayed substantially delayed endoplasmic reticulum to Golgi trafficking, which could be fully rescued upon Dymeclin re-expression. These findings indicate that Dymeclin is crucial for proper myelination and anterograde neuronal trafficking, two processes that are highly active during postnatal brain maturation. Show less

Smith-McCort dysplasia (SMC) is a rare autosomal recessive spondylo-epi-metaphyseal dysplasia with skeletal features identical to those of Dyggve-Melchior-Clausen syndrome (DMC) but with normal intelligence and no microcephaly. Although both syndromes were shown to result from mutations in the DYM gene, which encodes the Golgi protein DYMECLIN, a few SMC patients remained negative in DYM mutation screening. Recently, autozygosity mapping and exome sequencing in a large SMC family have allowed the identification of a missense mutation in RAB33B, another Golgi protein involved in retrograde transport of Golgi vesicles. Here, we report a novel RAB33B mutation in a second SMC case that leads to a marked reduction of the protein as shown by Western blot and immunofluorescence. These data confirm the genetic heterogeneity of SMC dysplasia and highlight the role of Golgi transport in the pathogenesis of SMC and DMC syndromes. Show less

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. Show less