Expression of kinase-deficient MEK2 ameliorates Pelizaeus-Merzbacher disease phenotypes in mice.

Pelizaeus-Merzbacher disease (PMD) is characterized as a congenital hypomyelinating disorder in oligodendrocytes, myelin-forming glial cells in the central nervous system (CNS). The responsible gene of PMD is plp1, whose multiplication, deletion, or mutation is associated with PMD. We previously reported that primary oligodendrocytes overexpressing proteolipid protein 1 (PLP1) do not have the ability to differentiate morphologically, whereas inhibition of mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) by its cognate siRNA or chemical inhibitor reverses their undifferentiated phenotypes. Here, we show that oligodendrocyte-specific expression of kinase-deficient dominant-inhibitory mutant (MEK2K101A) of MAPK/ERK kinase 2 (MEK2), as the direct upstream molecule of MAPK/ERK in PMD model mice, promotes myelination in CNS tissues. Expression of MEK2K101A in PMD model mice also improves Rotor-rod test performance, which is often used to assess motor coordination in a rodent model with neuropathy. These results suggest that in PMD model mice, MEK2K101A can ameliorate impairments of myelination and motor function and that the signaling through MAPK/ERK may involve potential therapeutic target molecules of PMD in vivo.

CNP deficiency causes severe hypomyelinating leukodystrophy in humans.

Myelin pathologies are an important cause of multifactorial, e.g., multiple sclerosis, and Mendelian, e.g., leukodystrophy, neurological disorders. CNP encodes a major component of myelin and its CNS expression is exclusive to myelin-forming oligodendrocytes. Deficiency of CNP in mouse causes a lethal white matter neurodegenerative phenotype. However, a corresponding human phenotype has not been described to date. Here, we describe a multiplex consanguineous family from Oman in which multiple affected members display a remarkably consistent phenotype of neuroregression with profound brain white matter loss. A novel homozygous missense variant in CNP was identified by combined autozygome/exome analysis. Immunoblot analysis suggests that this is a null allele in patient fibroblasts, which display abnormal F-actin organization. Our results suggest the establishment of a novel CNP-related hypomyelinating leukodystrophy in humans.

Pelizaeus-Merzbacher disease: cellular pathogenesis and pharmacologic therapy.

Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy that causes severe dysmyelination in the central nervous system in infancy and early childhood. Many previous studies showed that various proteolipid protein 1 (plp1) mutations, including duplications, point mutations, and deletions, lead to oligodendrocyte dysfunction in patients with PMD. PMD onset and clinical severity range widely, depending on the type of plp1 mutation. Patients with PMD exhibit a delayed mental and physical development phenotype, but specific pharmacological therapy and clinical treatment for PMD are not yet well established. This review describes PMD pathology and establishment of new clinical treatment for PMD. These findings support the development of a new therapy for PMD and these treatments may improve the quality of life in patients with PMD.

Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form.

Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus-Merzbacher-like disease (PMLD1, MIM# 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus-Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra- and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G>A) mutation, occurring in a highly conserved motif (SRPTEK) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a 'salt bridge network', crucial for a proper connexin-connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein.

High frequency of GJA12/GJC2 mutations in Turkish patients with Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease is an early onset dysmyelinating leukodystrophy. About 80% of PMD cases have been associated with duplications and mutations of the proteolipid protein 1 (PLP1) gene. Pelizaeus-Merzbacher-like disease is a genetically heterogeneous autosomal recessive disease and rarely caused by mutations in gap junction protein α12 (GJA12/GJC2) gene. The molecular basis of the disease was investigated in a cohort of 19 Turkish families. This study identified novel chromosomal rearrangements proximal and distal to, and exclusive of the PLP1 gene, showed equal frequencies of PLP1 and GJA12/GJC2 mutations at least in our cohort, and suggested further genetic heterogeneity.

Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum.

Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disease caused by mutations, deletions, or duplications of the proteolipid protein (PLP) gene. Mutant forms of PLP are retained in the endoplasmic reticulum (ER), and the resulting accumulation of mutant protein is thought to be a direct cause of oligodendrocyte cell death, which is the primary clinical feature of PMD. The molecular mechanisms underlying the toxicity of mutant PLP are however currently unknown. We report here that PMD-linked mutations of PLP are associated with the accelerated assembly of the protein into stable homooligomers that resemble mature, native PLP. Thus although WT PLP forms stable oligomers after an extended maturation period, most likely at the cell surface, mutant forms of PLP rapidly assemble into such oligomers at the ER. Using PLP mutants associated with diseases of varying severity, we show that the formation of stable oligomers correlates with the development of PMD. Based on these findings, we propose that the premature oligomerization of PLP in the ER of oligodendrocytes contributes to the pathology of PMD.

The molecular pathogenesis of Pelizaeus-Merzbacher disease.

In 1885, Pelizaeus described 5 boys in a single family with nystagmus, spastic quadriparesis, ataxia, and delay in cognitive development. In 1910, Merzbacher reexamined this family, which then included 14 affected individuals, including 2 girls, and found that all affected family members shared a common female ancestor. Also, he noted that the disease was passed exclusively through the female line without male-to-male transmission. Pathological analysis of brain tissue from one affected individual showed that most of the central white matter lacked histochemical staining for myelin, although there were occasional small regions of preserved myelin, giving the sections a "tigroid" appearance. The description of this family provides the clinical, genetic, and pathological basis for Pelizaeus-Merzbacher disease (PMD): an X-linked disorder of myelination classically characterized by nystagmus, spastic quadriparesis, ataxia, and cognitive delay in early childhood.