Missense mutation of MAL causes a rare leukodystrophy similar to Pelizaeus-Merzbacher disease.
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ABSTRACT:
SUBMITTER: Elpidorou M
PROVIDER: S-EPMC9259702 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by mutations or rearrangements in PLP1. It presents in infancy with nystagmus, jerky head movements, hypotonia and developmental delay evolving into spastic tetraplegia with optic atrophy and variable movement disorders. A clinically similar phenotype caused by recessive mutations in GJC2 is known as Pelizaeus-Merzbacher-like disease. Both genes encode proteins associated with myelin. We describe three siblings of a consanguineous family manifesting the typical infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Magnetic resonance imaging and spectroscopy were consistent with a demyelinating leukodystrophy. Using genetic linkage and exome sequencing, we identified a homozygous missense c.399C>G; p.S133R mutation in MAG. This gene, previously associated with hereditary spastic paraplegia, encodes myelin-associated glycoprotein, which is involved in myelin maintenance and glia-axon interaction. This mutation is predicted to destabilize the protein and affect its tertiary structure. Examination of the sural nerve biopsy sample obtained in childhood in the oldest sibling revealed complete absence of myelin-associated glycoprotein accompanied by ill-formed onion-bulb structures and a relatively thin myelin sheath of the affected axons. Immunofluorescence, cell surface labelling, biochemical analysis and mass spectrometry-based proteomics studies in a variety of cell types demonstrated a devastating effect of the mutation on post-translational processing, steady state expression and subcellular localization of myelin-associated glycoprotein. In contrast to the wild-type protein, the p.S133R mutant was retained in the endoplasmic reticulum and was subjected to endoplasmic reticulum-associated protein degradation by the proteasome. Our findings identify involvement of myelin-associated glycoprotein in this family with a disorder affecting the central and peripheral nervous system, and suggest that loss of the protein function is responsible for the unique clinical phenotype.
| S-EPMC4643626 | biostudies-literature
Project description:Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites. Human oligodendrocytes express the gap junction protein connexin47 (Cx47), which is encoded by the GJC2 gene. The autosomal recessive mutation hCx47M283T causes Pelizaeus-Merzbacher-like disease 1 (PMLD1), a progressive leukodystrophy characterized by hypomyelination, retarded motor development, nystagmus, and spasticity. We introduced the human missense mutation into the orthologous position of the mouse Gjc2 gene and inserted the mCx47M282T coding sequence into the mouse genome via homologous recombination in embryonic stem cells. Three-week-old homozygous Cx47M282T mice displayed impaired rotarod performance but unchanged open-field behavior. 10-15-day-old homozygous Cx47M282T and Cx47 null mice revealed a more than 80% reduction in the number of cells participating in glial networks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of mCx47M282T resulted in reduced MBP expression and astrogliosis in the cerebellum of ten-day-old mice which could also be detected in Cx47 null mice of the same age. Three-month-old homozygous Cx47M282T mice exhibited neither altered open-field behavior nor impaired rotarod performance anymore. Adult mCx47M282T expressing mice did not show substantial myelin alterations, but homozygous Cx47M282T mice, additionally deprived of connexin32, which is also expressed in oligodendrocytes, died within six weeks after birth and displayed severe myelin defects accompanied by astrogliosis and activated microglia. These results strongly suggest that PMLD1 is caused by the loss of Cx47 channel function that results in impaired panglial coupling in white matter tissue.
| S-EPMC3131295 | biostudies-literature
Project description:Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by PLP1 mutations. A similar autosomal-recessive phenotype, Pelizaeus-Merzbacher-like disease (PMLD), has been shown to be caused by homozygous mutations in GJC2 or HSPD1. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD in which linkage to PLP1, GJC2, and HSPD1 was excluded. Through genome-wide homozygosity mapping and mutation analysis, we demonstrated in all affected individuals a homozygous frameshift mutation that fully abrogates the main active domain of AIMP1, encoding ARS-interacting multifunctional protein 1. The mutation fully segregates with the disease-associated phenotype and was not found in 250 Bedouin controls. Our findings are in line with the previously demonstrated inability of mutant mice lacking the AIMP1/p43 ortholog to maintain axon integrity in the central and peripheral neural system.
| S-EPMC2997381 | biostudies-literature
Project description:Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder caused by mutations in the PLP1 gene, which encodes the proteolipid protein of myelinating oligodendroglia. PMD exhibits phenotypic variability that reflects its considerable genotypic heterogeneity, but all forms of the disease result in central hypomyelination associated with early neurologic dysfunction, progressive deterioration, and ultimately death. PMD has been classified into three major subtypes, according to the age of presentation: connatal PMD, classic PMD, and transitional PMD, combining features of both connatal and classic forms. Two other less severe phenotypes were subsequently described, including the spastic paraplegia syndrome and PLP1-null disease. These disorders may be associated with duplications, as well as with point, missense, and null mutations within the PLP1 gene. A number of clinically similar Pelizaeus-Merzbacher-like disorders (PMLD) are considered in the differential diagnosis of PMD, the most prominent of which is PMLD-1, caused by misexpression of the GJC2 gene encoding connexin-47. No effective therapy for PMD exists. Yet, as a relatively pure central nervous system hypomyelinating disorder, with limited involvement of the peripheral nervous system and little attendant neuronal pathology, PMD is an attractive therapeutic target for neural stem cell and glial progenitor cell transplantation, efforts at which are now underway in a number of centers internationally.
| S-EPMC8167836 | biostudies-literature
Project description:ObjectivePelizaeus-Merzbacher-like disease is a rare hypomyelinating leukodystrophy caused by autosomal recessive mutations in GJC2, encoding a gap junction protein essential for production of a mature myelin sheath. A previously identified GJC2 mutation (c.-167A>G) in the promoter region is hypothesized to disrupt a putative SOX10 binding site; however, the lack of additional mutations in this region and contradictory functional data have limited the interpretation of this variant.MethodsWe describe two independent Pelizaeus-Merzbacher-like disease families with a novel promoter region mutation and updated in vitro functional assays.ResultsA novel GJC2 mutation (c.-170A>G) in the promoter region was identified in Pelizaeus-Merzbacher-like disease patients. In vitro functional assays using human GJC2 promoter constructs demonstrated that this mutation and the previously described c.-167A>G mutation similarly diminished the transcriptional activity driven by SOX10 and the binding affinity for SOX10.InterpretationThese findings support the role of GJC2 promoter mutations in Pelizaeus-Merzbacher-like disease. GJC2 promoter region mutation screening should be included in the evaluation of patients with unexplained hypomyelinating leukodystrophies.
| S-EPMC4183365 | biostudies-literature
Project description:Mutations in PLP1, the gene that encodes proteolipid protein (PLP), result in failure of myelination and neurological dysfunction in the X-chromosome-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD)1,2. Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. Patients who lack PLP1 expression, and Plp1-null mice, can display comparatively mild phenotypes, suggesting that PLP1 suppression might provide a general therapeutic strategy for PMD1,3-5. Here we show, using CRISPR-Cas9 to suppress Plp1 expression in the jimpy (Plp1jp) point-mutation mouse model of severe PMD, increased myelination and restored nerve conduction velocity, motor function and lifespan of the mice to wild-type levels. To evaluate the translational potential of this strategy, we identified antisense oligonucleotides that stably decrease the levels of Plp1 mRNA and PLP protein throughout the neuraxis in vivo. Administration of a single dose of Plp1-targeting antisense oligonucleotides in postnatal jimpy mice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function and extended lifespan up to an eight-month end point. These results suggest that PLP1 suppression could be developed as a treatment for PMD in humans. More broadly, we demonstrate that oligonucleotide-based therapeutic agents can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, establishing a new pharmaceutical modality for myelin disorders.
| S-EPMC7810164 | biostudies-literature
Project description:Major gaps in our understanding of the leukodystrophies result from their rarity and the lack of tissue for the interdisciplinary studies required to extend our knowledge of the pathophysiology of the diseases. This study details the natural evolution of changes in the CNS of the shaking pup (shp), a model of the classical form of the X-linked disorder Pelizaeus-Merzbacher disease, in particular in glia, myelin, and axons, which is likely representative of what occurs over time in the human disease. The mutation in the proteolipid protein gene, PLP1, leads to a delay in differentiation, increased cell death, and a marked distension of the rough endoplasmic reticulum in oligodendrocytes. However, over time, more oligodendrocytes differentiate and survive in the spinal cord leading to an almost total recovery of myelination, In contrast, the brain remains persistently hypomyelinated. These data suggest that shp oligodendrocytes may be more functional than previously realized and that their early recruitment could have therapeutic value.
| S-EPMC4492172 | biostudies-other
Project description:We investigated the changes in the overall gene expression in MO3.13 cells induced by PLP1A243V and piracetam using RNA microarray analyses. We compared gene expression between PLP1WT and PLP1A243V and the expression profile in MO3.13 stably expressing PLP1A243V with/without piracetam.
2018-12-19 | GSE124034 | GEO
Project description:Pelizaeus-Merzbacher-Like Disease 1 is a genetic disorder affecting the central nervous system with an autosomal recessive inheritance pattern. It is a rare genetic disorder that affects the central nervous system. In this report, we demonstrated the clinical and paraclinical features of an Iranian consanguine pedigree with suspected hypomyelinating leukodystrophy, without any defined diagnosis. The proband, a 15-month-old girl, visited the Razi pathobiology and medical genetic laboratory of Karaj, where the study was conducted in 2020. Following whole-exome sequencing analysis of the proband and segregation analysis, a novel pathogenic mutation was discovered. GJC2 (NM_020435.4):c.1096dupG was found to be homozygous in the proband and heterozygous in both parents. This mutation was in the coding region of the protein, which results in D366Gfs*126 (p.Asp366GlyfsTer126). The site of mutation was at the 3' region of the connexin superfamily domain. The frameshift results in a different peptide sequence of the C-terminal and extended protein. Our findings led to the diagnosis of the proband's disease as Pelizaeus-Merzbacher-Like Disease 1 and led to the end of the diagnostic odyssey. We provided effective genetic counseling through the identification of a novel pathogenic mutation in gap junction protein C2 in this family and suggested preimplantation genetic diagnosis for the next pregnancy. Furthermore, our findings confirmed the association of GJC2 mutations with PMLD1. This discovery added to the repertoire of genetic mutations of Pelizaeus-Merzbacher-Like Disease 1. This knowledge could be applied for expanded carrier screening of other families, especially for Iranian consanguine marriages.
| S-EPMC8611227 | biostudies-literature
Project description:Pelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation.
| S-EPMC4050482 | biostudies-literature