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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Variants in ARPP21 were initially proposed to synergize with GLT8D1 in ALS pathogenesis. However, in a Chinese case-control study of 512 ALS patients and 3210 controls, 25 rare ARPP21 variants showed no significant association (PMID:31653410). Similarly, whole-exome and whole-genome sequencing of 81 familial and 618 sporadic ALS cases (n = 699) identified no novel or enriched protein-altering ARPP21 variants (PMID:33581934).
No segregation data or functional assays supporting a pathogenic role for ARPP21 in Amyotrophic lateral sclerosis were reported. Taken together, current genetic and experimental evidence refutes a role for ARPP21 in ALS etiology. Key take-home: ARPP21 testing is not recommended in clinical ALS genetic screening panels.
Gene–Disease AssociationRefutedTwo large case-control cohorts (512 ALS patients vs 3210 controls [PMID:31653410] and 81 familial + 618 sporadic ALS cases [PMID:33581934]) found no significant enrichment of rare ARPP21 variants. Genetic EvidenceLimitedNo pathogenic ARPP21 variants identified in a combined >1200 ALS cases; no segregation or case-level evidence. Functional EvidenceLimitedNo functional or experimental studies reported supporting ARPP21 involvement in ALS. |