PLP1 – Pelizaeus-Merzbacher Spectrum Disorder

Pelizaeus-Merzbacher spectrum disorder is a rare X-linked recessive leukodystrophy caused by pathogenic variants in the proteolipid protein 1 gene (PLP1), characterized by congenital nystagmus, spasticity, hypomyelination on MRI, and progressive neurological decline. Age at onset ranges from the connatal form with early hypotonia and respiratory failure to milder spastic paraplegia type 2 in later childhood. Oligodendrocyte loss due to disturbed PLP1 trafficking underlies the central dysmyelination (PMID:7683951).

Molecular diagnostics across >300 unrelated patients reveal PLP1 gene duplications in ~62% of cases and intragenic point mutations in ~38% (n=82 families) detected by quantitative PCR or comparative multiplex PCR ([PMID:10417279]). Single‐base substitutions, small insertions/deletions, splice‐site changes, and initiation codon variants have been documented in diverse populations, confirming a broad mutational spectrum.

Family‐based and cohort studies report robust segregation of both duplications and point mutations. Intragenic PLP1 mutations encoding missense (e.g., c.661G>T (p.Gly221Cys)), nonsense, and frameshift alleles co-segregate with PMD across multiple pedigrees, with obligate carrier mothers and affected male relatives identified in >30 families (PMID:1376966; PMID:15712223).

Variant classes include large tandem duplications of the entire PLP1 locus, missense substitutions clustering in conserved transmembrane domains (e.g., p.Pro216Leu; p.Leu224Phe), null alleles affecting initiation codons or splicing, and in-frame deletions such as exon 5 loss (c.696+1G>A) leading to hypomyelinating phenotypes. Genotype-phenotype correlations demonstrate that gain-of-function missense changes often produce severe connatal forms, whereas null and DM20-specific mutations yield milder spastic paraplegia (PMID:11093273).

Functional assays in oligodendrocyte models and patient cells show that severe PMD‐associated PLP1 mutants are retained in the endoplasmic reticulum (ER), triggering unfolded protein response and apoptotic pathways, whereas milder SPG2 alleles partly escape ER quality control but have impaired lipid raft and cholesterol interactions ([PMID:8696336]; PMID:17093095).

Transgenic and mouse models further confirm pathogenicity: the jimpy mutation exerts dominant-negative effects on oligodendrocyte survival despite co-expression of wild-type PLP, and complementation studies restore myelin compaction only when mutant PLP retention is alleviated (PMID:7538670).

Although PLP1 is the primary locus for PMD, mutations in other genes such as RARS may produce PMD-like hypomyelination, underscoring the need for comprehensive exome analysis in patients lacking PLP1 defects (PMID:28905880).

Key Take-home: Genetic testing for PLP1 duplications and point mutations enables definitive diagnosis of Pelizaeus-Merzbacher spectrum disorder, informs recurrence risk, and guides potential molecular therapies targeting ER-associated misfolding.

References

• Human molecular genetics • 1993 • A missense mutation in the proteolipid protein gene responsible for Pelizaeus-Merzbacher disease in a Japanese family PMID:7683951
• American Journal of Human Genetics • 1999 • Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher Disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not PMID:10417279
• Human mutation • 2005 • Seventeen novel PLP1 mutations in patients with Pelizaeus-Merzbacher disease PMID:15712223
• European Journal of Human Genetics • 2000 • Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations PMID:11093273
• Nature Genetics • 1996 • A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease PMID:8696336
• Proceedings of the National Academy of Sciences USA • 1995 • Dominant-negative action of the jimpy mutation in mice complemented with an autosomal transgene for myelin proteolipid protein PMID:7538670
• European Journal of Human Genetics • 2017 • Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease PMID:28905880

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