CHMP2B – Amyotrophic Lateral Sclerosis

In multiple case‐series of predominantly lower motor neuron ALS, heterozygous missense CHMP2B variants were identified in approximately 1% of patients, with 4 probands in a cohort of 433 North of England ALS cases and a novel p.Arg69Gln variant in sporadic PMA/ALS (5 probands total) (PMID:20352044, PMID:23155438). These variants, including c.311C>A (p.Thr104Asn), were absent from >500 controls and observed in one individual with a positive family history but lack formal segregation data. Inheritance is autosomal dominant, and the limited number of unrelated probands and minimal familial segregation underpins a Limited gene–disease association.

Functional studies demonstrate that CHMP2B missense mutations impair ESCRT‐III function and autophagy: transfected p.Thr104Asn in HEK‐293 and COS‐7 cells induces large cytoplasmic vacuoles, aberrant CD63 localization, and elevated LC3-II levels, consistent with autophagy blockade (PMID:18418046, PMID:22521643). Neuron‐restricted expression of CHMP2B^intron5 in mice causes synaptopathy, neuromuscular junction degeneration, and muscle fiber type switching recalling ALS pathology (PMID:35454086). The concordance of in vitro and in vivo models supports a dominant‐negative mechanism, though evidence remains insufficient for definitive clinical validity.

Key Take-home: Rare heterozygous CHMP2B missense variants have limited genetic support as ALS risk factors but are mechanistically linked to ESCRT/autophagy dysfunction, suggesting potential utility in targeted genetic panels for LMN-predominant ALS.

References

• PloS one • 2010 • Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PMID:20352044
• PloS one • 2012 • Genetic overlap between apparently sporadic motor neuron diseases. PMID:23155438
• Cell cycle (Georgetown, Tex.) • 2008 • ESCRT functions in autophagy and associated disease. PMID:18418046
• Biochemical and biophysical research communications • 2012 • The functional analysis of the CHMP2B missense mutation associated with neurodegenerative diseases in the endo-lysosomal pathway. PMID:22521643
• Biomolecules • 2022 • Alteration of the Neuromuscular Junction and Modifications of Muscle Metabolism in Response to Neuron-Restricted Expression of the CHMP2Bintron5 Mutant in a Mouse Model of ALS-FTD Syndrome. PMID:35454086

Evidence Based Scoring (AI generated)