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Dymeclin deficiency causes postnatal microcephaly, hypomyelination and reticulum-to-Golgi trafficking defects in mice and humans

Research output: Contribution to journalArticle

Nina Dupuis, Assia Fafouri, Aurélien Bayot, Manoj Kumar, Tifenn Lecharpentier, Gareth Ball, David Edwards, Véronique Bernard, Pascal Dournaud, Séverine Drunat, Marie Vermelle-Andrzejewski, Catheline Vilain, Marc Abramowicz, Julie Désir, Jacky Bonaventure, Nelly Gareil, Gaelle Boncompain, Zsolt Csaba, Franck Perez, Sandrine Passemard & 2 more Pierre Gressens, Vincent El Ghouzzi

Original languageEnglish
JournalHuman Molecular Genetics
DOIs
Publication statusE-pub ahead of print - 2015

King's Authors

Abstract

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, that 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.

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