PRPH – Amyotrophic Lateral Sclerosis

PRPH encodes peripherin, a neuronal intermediate filament protein predominantly expressed in motor neurons (PRPH), and heterozygous and homozygous PRPH variants have been identified in amyotrophic lateral sclerosis with apparent Autosomal dominant inheritance in most cases (Amyotrophic lateral sclerosis). Rare PRPH variants have been reported in five unrelated ALS probands (PMID:15446584, PMID:20363051, PMID:15322088): a homozygous missense c.421G>T (p.Asp141Tyr) in one patient (PMID:15446584), heterozygous missense p.Arg133Pro and p.Asp141Tyr in two sporadic cases (PMID:20363051), and a heterozygous truncating c.229del (p.Arg77fs) in another case (PMID:15322088). No segregation data within families are available. These alleles were absent from at least 245 and 380 control chromosomes (PMID:20363051; PMID:15322088). The total of five probands with deleterious PRPH alleles supports a Limited genetic evidence level.

Functional assays demonstrate that p.Asp141Tyr peripherin forms cytoplasmic aggregates rather than a normal filamentous network in transfected cells and resists rescue by neurofilament light chain, mirroring pathological inclusions observed in patient spinal motor neurons (PMID:15446584). Transgenic mice overexpressing peripherin splice variants, particularly the neurotoxic isoform Per 61, develop selective motor neuron degeneration consistent with an ALS phenotype (PMID:12642616). These data indicate that mutant peripherin disrupts neurofilament assembly, a plausible pathogenic mechanism. However, the small number of reported ALS cases and lack of familial segregation warrant further study. Key take-home: rare PRPH variants may contribute to ALS risk, but current evidence remains limited for routine diagnostic use.

References

• Brain pathology • 2004 • A pathogenic peripherin gene mutation in a patient with amyotrophic lateral sclerosis. PMID:15446584
• The Journal of biological chemistry • 2004 • A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis. PMID:15322088
• Neurobiology of aging • 2011 • A novel peripherin gene (PRPH) mutation identified in one sporadic amyotrophic lateral sclerosis patient. PMID:20363051
• The Journal of cell biology • 2003 • A neurotoxic peripherin splice variant in a mouse model of ALS. PMID:12642616

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