HNRNPA2B1 – Amyotrophic Lateral Sclerosis

Heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) was first implicated in multisystem proteinopathy syndromes that include amyotrophic lateral sclerosis (ALS), frontotemporal dementia, inclusion body myopathy, and Paget disease of bone, based on exome sequencing in three families with MSP featuring ALS phenotypes (PMID:24119545). However, targeted sequencing of HNRNPA2B1 in multiple independent ALS cohorts has consistently failed to identify pathogenic variants, with no mutations detected in 17 MSP/FTLD-ALS patients (PMID:24119545), 135 familial and >1000 sporadic ALS patients in The Netherlands (PMID:24612671), 161 Taiwanese ALS patients including 30 familial cases (PMID:24908169), and 200 Australian ALS cases including both familial and sporadic forms (PMID:29131108).

No segregation data support HNRNPA2B1 variants in ALS pedigrees, and no functional studies have evaluated hnRNPA2/B1 in ALS models or patient‐derived tissues. The absence of identified variants across >1 500 ALS patients and lack of experimental concordance indicate limited genetic and biological evidence for HNRNPA2B1 as an ALS-causing gene.

References

• Neurobiology of aging • 2014 • hnRNPA2B1 and hnRNPA1 mutations are rare in patients with "multisystem proteinopathy" and frontotemporal lobar degeneration phenotypes PMID:24119545
• Neurobiology of aging • 2014 • No mutations in hnRNPA1 and hnRNPA2B1 in Dutch patients with amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy PMID:24612671
• Neurobiology of aging • 2014 • Extensive molecular genetic survey of Taiwanese patients with amyotrophic lateral sclerosis PMID:24908169
• Neuro-degenerative diseases • 2017 • Genetic and Pathological Assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in Familial and Sporadic Amyotrophic Lateral Sclerosis PMID:29131108

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