VAPB – Amyotrophic Lateral Sclerosis Type 8

VAPB encodes vesicle-associated membrane protein-associated protein B, mutations in which cause autosomal dominant amyotrophic lateral sclerosis type 8 (ALS8). The founding P56S variant was first identified in eight Brazilian families, spanning over 1,500 individuals with ~200 affected carriers of the c.166C>T (p.Pro56Ser) allele (PMID:16187141). A subsequent North American sporadic case confirmed the mutation’s role in ALS8 (PMID:29560381).

Genetic studies demonstrate dominant inheritance, with segregation of P56S across multiple generations in eight families and an additional de novo report. Beyond P56S, rare variants including c.137C>T (p.Thr46Ile), c.434C>T (p.Ala145Val), and c.476CTT (p.Ser160del) have been detected but remain less prevalent. The predominance of missense changes affecting the MSP domain underscores critical structural disruption.

Functional assays reveal that P56S-VAPB aggregates in non-ER compartments, abrogates unfolded protein response (UPR) signaling, and exerts dominant-negative effects on wild-type VAPB, leading to ER stress and impaired proteostasis (PMID:16891305; PMID:19183264). Structural studies confirm loss of MSP-domain immunoglobulin fold and solubility (PMID:20377183).

Animal models in zebrafish, Drosophila, and murine systems recapitulate motor deficits and neuromuscular junction abnormalities upon VAPB knockdown or P56S knock-in, supporting a loss-of-function pathogenic mechanism with dominant-negative aggregation (PMID:18523548; PMID:26362257). Overexpression studies further delineate impaired axonal transport, ER–Golgi trafficking defects, and exacerbation of ER stress.

No robust evidence disputes the VAPB–ALS8 link, though overexpression of P56S-VAPB alone does not always induce neurodegeneration in SOD1G93A mice, suggesting modifier factors in vivo (PMID:23281774).

In sum, VAPB P56S fulfills criteria for a definitive gene–disease association: extensive familial segregation, recurrent founder effect, and concordant functional models. Genetic testing for c.166C>T (p.Pro56Ser) and rare MSP-domain variants informs diagnosis, and understanding VAPB-mediated UPR impairment may guide targeted therapeutics.

Key take-home: VAPB mutations cause autosomal dominant ALS8 via dominant-negative loss of UPR function and aggregate formation, supporting their clinical utility in diagnosis and research.

References

• Human genetics • 2005 • A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population. PMID:16187141
• Annals of clinical and translational neurology • 2018 • Nucleocytoplasmic transport defect in a North American patient with ALS8. PMID:29560381
• The Journal of biological chemistry • 2006 • Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8). PMID:16891305
• PloS one • 2008 • A Drosophila model of ALS: human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PMID:18523548

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