PLP1 – Classic Pelizaeus-Merzbacher Disease

Classic Pelizaeus-Merzbacher disease (PMD) is an X-linked hypomyelinating leukodystrophy characterized by early-onset nystagmus, hypotonia, and psychomotor delay. The disease is caused by mutations in PLP1, which encodes the proteolipid protein critical for compact myelin formation in the central nervous system. Affected males typically present in the first year of life with pendular eye oscillations, head bobbing, and delayed gross motor milestones. Female carriers may exhibit variable, often milder, spastic paraplegia due to X-chromosome inactivation. Brain MRI demonstrates diffuse hypomyelination with thinning of the corpus callosum. Diagnosis is established through molecular testing of PLP1 for point mutations, copy-number changes, and splicing variants.

The missense variant c.655G>T (p.Val219Phe) in PLP1 was first identified in a four-generation family and co-segregated with PMD in 19 affected males and obligate carriers (PMID:1715570). This allele shows full penetrance in hemizygous males and is absent in unaffected relatives. Independent case reports, including an Iranian boy presenting with nystagmus and hypotonia, confirm PLP1 involvement in classic PMD (PMID:23056820). PLP1 duplications account for 60–70% of PMD cases, while rare loss-of-function and splice-altering mutations contribute to the phenotypic spectrum.

PMD follows an X-linked recessive inheritance pattern, with symptomatic males and carrier females. Segregation of PLP1 alleles in large pedigrees provides strong genetic evidence for pathogenicity. Case-level data include the Iranian proband whose clinical features and hypomyelination were confirmed by PLP1 sequencing (PMID:23056820). Over 200 pathogenic PLP1 variants have been reported, including missense, nonsense, frameshift, splice-site, and copy number changes. No common founder variants are established, but hotspots in transmembrane regions correlate with severe phenotypes.

Functional studies in jimpy mice harboring Plp1 null alleles demonstrate a dominant-negative effect, with oligodendrocyte death and dysmyelination that is rescued by a wild-type PLP1 transgene (PMID:7538670). In vitro assays reveal that severe missense mutants (e.g., p.Ala242Val) accumulate in the endoplasmic reticulum, activate the unfolded protein response, and trigger apoptosis (PMID:19825935). Milder mutants are cleared rapidly or escape ER retention, correlating with disease severity. Disruption of PLP1/DM20 splicing by intronic mutations alters the PLP1:DM20 ratio and impairs myelin stability in knock-in models (PMID:23344956).

Pathogenic PLP1 variants cause protein misfolding, ER stress, and impaired trafficking to myelin membranes, leading to oligodendrocyte dysfunction. The toxic gain-of-function and haploinsufficiency mechanisms converge to produce diffuse hypomyelination. Concordant evidence from animal models, cellular assays, and human pedigrees underpins the gene-disease link.

PLP1 genetic testing enables definitive diagnosis, guides prognostic counselling, and informs carrier detection in X-linked families. Comprehensive analysis, including sequencing and copy-number assessment, is essential given the diverse variant types. Early recognition of nystagmus and hypotonia should prompt targeted PLP1 evaluation to facilitate clinical management and eligibility for emerging therapies. Key take-home: PLP1 mutation analysis is clinically indispensable for diagnosing and managing classic Pelizaeus-Merzbacher disease.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1991 • Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid. PMID:1715570
• Iranian journal of pediatrics • 2011 • Pelizaeus-merzbacher disease: the first genetically approved case report from iran. PMID:23056820
• Proceedings of the National Academy of Sciences of the United States of America • 1995 • Dominant-negative action of the jimpy mutation in mice complemented with an autosomal transgene for myelin proteolipid protein. PMID:7538670
• Journal of cell science • 2009 • Differences in endoplasmic-reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein. PMID:19825935
• The Journal of biological chemistry • 2013 • Depletion of molecular chaperones from the endoplasmic reticulum and fragmentation of the Golgi apparatus associated with pathogenesis in Pelizaeus-Merzbacher disease. PMID:23344956

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