VAPB – Amyotrophic Lateral Sclerosis

Vesicle-associated membrane protein-associated protein B (VAPB) was first implicated in an autosomal dominant form of motor neuron disease (ALS8) when a missense mutation (P56S) was identified in a large Brazilian kindred with late-onset spinal muscular atrophy and atypical amyotrophic lateral sclerosis (PMID:15372378). Haplotype analysis across seven kindreds suggested a founder effect for the c.166C>T (p.Pro56Ser) variant. Subsequent reports confirmed P56S in diverse populations, including a three-generation Chinese family (PMID:26566915) and a novel P56H mutation co-segregating in a Chinese Han pedigree (PMID:28993872).

Autosomal dominant inheritance is established by segregation of c.166C>T (p.Pro56Ser) in multiple multiplex families, with at least seven affected relatives across Brazilian and Chinese pedigrees. Additional VAPB variants have been reported: c.137C>T (p.Thr46Ile) in a familial ALS case (PMID:23446633), and c.700G>A (p.Val234Ile) in a C9orf72-repeat expansion carrier (PMID:22878164). The recurrent P56S allele accounts for ~43.6% of familial ALS in one Brazilian cohort (PMID:27978769).

Genetic evidence reaches a strong tier: c.166C>T (p.Pro56Ser) has been identified in more than seven probands across seven families with clear autosomal dominant segregation and a founder effect, supplemented by single-kindred reports of T46I and V234I.

Functional characterization demonstrates that P56S-VAPB abrogates unfolded protein response (UPR) by forming cytosolic aggregates and sequestering wild-type VAPB, reducing ER stress resilience in cell models (PMID:16891305; PMID:19183264). In Drosophila, P58S (equivalent to P56S) acts as a dominant negative at the neuromuscular junction via BMP signaling disruption (PMID:18523548). Loss-of-function studies in zebrafish and mice reveal motor deficits and mild late-onset phenotypes that cannot be rescued by mutant VAPB, indicating haploinsufficiency contributes to disease risk (PMID:23446633).

Proteostasis defects are further supported by impaired proteasome activity upon VAPB aggregation (PMID:21998752), mislocalization of ER–Golgi tethering proteins such as YIF1A (PMID:23736259), and knock-in mice expressing P56S-VAPB display age-dependent motor impairments, ER stress induction, and autophagic responses in motor neurons (PMID:26362257). Proteomic profiling of ER domains also shows altered composition in P56S-VAPB cells (PMID:32376919).

Conflicting data arise from studies of sporadic ALS cohorts in Southern Italy and in Sweden/Portugal/Iceland, where VAPB variants (e.g., p.Asp130Glu, p.Met170Ile) occurred at similar frequencies in patients and controls without clear segregation (PMID:16729899; PMID:23971766). These findings suggest that many VAPB variants may be benign or of reduced penetrance.

Integration of genetic and functional evidence supports VAPB P56S as a pathogenic, autosomal dominant cause of ALS8 through a dominant-negative and haploinsufficiency mechanism. While rare in the general population, the P56S founder allele in Brazilian families and independent occurrences worldwide highlight its diagnostic relevance. Key take-home: VAPB c.166C>T (p.Pro56Ser) testing informs familial ALS8 diagnosis and underscores ER proteostasis as a therapeutic target.

References

• American journal of human genetics • 2004 • A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. PMID:15372378
• Journal of neurology • 2016 • Atypical familial amyotrophic lateral sclerosis with initial symptoms of pain or tremor in a Chinese family harboring VAPB-P56S mutation. PMID:26566915
• Journal of neurology • 2017 • A novel mutation of VAPB in one Chinese familial amyotrophic lateral sclerosis pedigree and its clinical characteristics. PMID:28993872
• Neurobiology of aging • 2012 • VAPB and C9orf72 mutations in 1 familial amyotrophic lateral sclerosis patient. PMID:22878164
• Human molecular genetics • 2013 • Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis. PMID:23446633
• 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
• Journal of neurochemistry • 2009 • ALS-linked P56S-VAPB, an aggregated loss-of-function mutant of VAPB, predisposes motor neurons to ER stress-related death by inducing aggregation of co-expressed wild-type VAPB. PMID:19183264
• PloS one • 2008 • A Drosophila model of ALS: human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PMID:18523548
• PloS one • 2011 • Accumulation of wildtype and ALS-linked mutated VAPB impairs activity of the proteasome. PMID:21998752
• The EMBO journal • 2013 • The ALS8 protein VAPB interacts with the ER-Golgi recycling protein YIF1A and regulates membrane delivery into dendrites. PMID:23736259
• Human molecular genetics • 2015 • Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response. PMID:26362257
• Scientific reports • 2020 • Proteomics-Based Approach Identifies Altered ER Domain Properties by ALS-Linked VAPB Mutation. PMID:32376919
• Journal of negative results in biomedicine • 2006 • Sporadic ALS is not associated with VAPB gene mutations in Southern Italy. PMID:16729899
• Amyotrophic lateral sclerosis & frontotemporal degeneration • 2013 • No association between VAPB mutations and familial or sporadic ALS in Sweden, Portugal and Iceland. PMID:23971766

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