Submission Details

PRPH was first reported in relation to amyotrophic lateral sclerosis 7(ALS) in 2004 (Leung et al., PMID: 15446584). This individual had a homozygous missense variant, Asp141Tyr, which has since been found to occur at a frequency of 0.3% (based on the total gnomADv2.1.1 non-neuro population) and is not considered plausibly causative of ALS for this curation. Since 2004 rare heterozygous variants have been identified in additional ALS patients and an autosomal dominant mechanism has been considered here. PRPH encodes peripherin, a neuronal-specific intermediate filament protein expressed predominantly in the peripheral nervous system. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 4 plausibly causative, rare variants have been reported in relation to ALS (including frameshift and missense variants). Variants in this gene have been reported in at least 4 probands in 3 publications (PMIDs: 15322088, 25299611, 26742954). Experimentally, this gene-disease relationship is supported by its expression in the nerous system (PMID: 3339087) and the fact that it is a major component found in inclusions of patients with ALS (PMID: 14675609). Additionally, an mouse model with overexpression of PRPH (PMID: 15132161) showed massive and selective degeneration of motor axons during aging. In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.