PLP1 – hereditary spastic paraplegia 2

The PLP1 gene encodes proteolipid protein 1, the principal protein in central nervous system myelin. Mutations in PLP1 cause a spectrum of X-linked leukodystrophies, ranging from Pelizaeus–Merzbacher disease to spastic paraplegia type 2 (SPG2), formally referred to as hereditary spastic paraplegia 2. SPG2 presents with predominant lower limb spasticity, gait disturbance and variable cognitive involvement in affected males, with milder manifestation in heterozygous females.

SPG2 follows an X-linked recessive inheritance pattern. Initial reports described a family with 3 affected males and 1 symptomatic female carrier harboring a unique c.442C>T (p.His148Tyr) variant segregating with late-onset spasticity (PMID:10319897). Subsequent studies of 28 unrelated SPG2 families confirmed 4 distinct point mutations in PLP1 segregating with disease (PMID:11093273).

The PLP1 variant spectrum in SPG2 includes missense substitutions within transmembrane domains (e.g., p.Ala30Pro, p.Tyr263Cys), splice-site changes (e.g., c.453+28_453+46del), frameshifts (e.g., p.Gly120fs) and whole-gene duplications or deletions. The recurrent c.442C>T (p.His148Tyr) has been reported in multiple pedigrees, indicating a potential mutational hotspot.

Functional assays demonstrate that SPG2-associated PLP1 mutants are misfolded, undergo endoplasmic reticulum retention, and trigger unfolded protein response, leading to oligodendrocyte dysfunction and dysmyelination. Cellular models show rescue of PLP1 trafficking with wild-type DM20 expression, supporting a dominant-negative mechanism for severe alleles and haploinsufficiency for milder ones (PMID:8696336; PMID:16844304).

No studies have directly refuted the PLP1–SPG2 association. Reported phenotypic variability among carriers is attributed to X-inactivation and allele-specific effects rather than locus heterogeneity.

Collectively, PLP1 fulfills criteria for a definitive gene–disease relationship with hereditary spastic paraplegia 2, supported by extensive segregation in over 28 families, diverse pathogenic variants, and concordant functional data. Key take-home: PLP1 mutation screening is essential for accurate diagnosis of SPG2, enabling informed genetic counseling and potential future targeted therapies.

References

• Annals of human genetics • 2000 • Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease. PMID:11093273
• Annals of Neurology • 1999 • Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members. PMID:10319897
• Nature Genetics • 1996 • A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. PMID:8696336
• Neuroscience • 2006 • Aberrant trafficking of a proteolipid protein in a mild Pelizaeus-Merzbacher disease. PMID:16844304

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