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

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, 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.

Golgi trafficking defects in postnatal microcephaly: The evidence for “Golgipathies”

“…In line with this finding, recent data from our group show a significant reduction in white matter volume associated with defects in the way the myelin sheath is wrapped, and a reduced thickness of myelinated axons in Dym-/mutant mice (Dupuis et al, 2015). Interestingly, Dym-deficient neurons display a fragmented Golgi apparatus and impaired ER-to-Golgi trafficking (Dupuis et al, 2015). However, an impairment of the retrograde transport of vesicles from the Golgi to the ER has also been suggested in Dym-/-mouse embryonic fibroblasts (Osipovich et al, 2008).…”

“…Brain MRI in DMC patients with a truncating mutation in DYM reveals a marked thinning of the corpus callosum and brain stem (Dupuis et al, 2015). In line with this finding, recent data from our group show a significant reduction in white matter volume associated with defects in the way the myelin sheath is wrapped, and a reduced thickness of myelinated axons in Dym-/mutant mice (Dupuis et al, 2015). Interestingly, Dym-deficient neurons display a fragmented Golgi apparatus and impaired ER-to-Golgi trafficking (Dupuis et al, 2015).…”

“…3.2.6 Dyggve-Melchior-Clausen syndrome and DYMECLIN Dyggve-Melchior-Clausen syndrome (DMC, MIM #223800) is an autosomal recessive skeletal dysplasia associated with POM and intellectual disability, and caused by loss-offunction mutations in the DYM gene encoding DYMECLIN, a Golgi protein involved in intracellular trafficking (Dimitrov et al, 2009;Osipovich et al, 2008;Paupe et al, 2004). Brain MRI in DMC patients with a truncating mutation in DYM reveals a marked thinning of the corpus callosum and brain stem (Dupuis et al, 2015). In line with this finding, recent data from our group show a significant reduction in white matter volume associated with defects in the way the myelin sheath is wrapped, and a reduced thickness of myelinated axons in Dym-/mutant mice (Dupuis et al, 2015).…”

“…The implication of several Golgi-associated RABs in the pathophysiology of POM highlights the central role of the Golgi apparatus in dynamically receiving and generating specific membrane vesicles both in large quantities and in a highly controlled manner. Thus, one possible mechanism responsible for the development of POM could be an insufficient supply of synaptic and/or oligodendrocytic cargos due to a defective secretory pathway in these highly demanding cells (Dupuis et al, 2015). Such a defect may be due to ineffective transport, alteration in cargo maturation (e.g.…”

A novel iterative mixed model to remap three complex orthopedic traits in dogs

“…Dyggve–Melchior–Clausen syndrome and Smith-McCort dysplasia are recessive spondyloepimetaphyseal dysplasias caused by loss-of-function mutations in dymeclin ( DYN) [57–59], the candidate gene closest to the marker at CFA7:79,570,691 associated with RCCL. Dymeclin is involved in Golgi trafficking and DYN mutations cause delayed endoplasmic reticulum to Golgi trafficking [60]. There has been a long debate as to whether excessive caudal slope of the proximal tibia, that might result from a local dysplasia, places excessive overload on a cranial cruciate ligament susceptible to rupture [61].…”