CYLD – Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS; MONDO:0004976) is a progressive neurodegenerative disorder characterized by motor neuron loss. CYLD (HGNC:2584) has been implicated in ALS through a single large autosomal dominant kindred. A missense variant c.2155A>G (p.Met719Val) segregates with disease in two affected family members (PMID:32185393). The locus on chromosome 16p12.1-q12.2 showed genome-wide significant linkage, and CYLD Met719Val falls within this critical interval.

Inheritance is autosomal dominant with segregation of the c.2155A>G variant in two affected relatives (PMID:32185393). Only one family has been reported, yielding limited genetic evidence. A single missense variant is described, and no additional unrelated probands are available.

Functional studies support a gain-of-function mechanism. Primary mouse neurons expressing CYLD Met719Val exhibit increased cytoplasmic TDP-43 localization and axonal shortening, recapitulating ALS pathology (PMID:32185393). Enzymatic assays demonstrate significantly increased K63-deubiquitinase activity (P = 0.005), and overexpression in HEK293 cells leads to enhanced NF-κB inhibition and impaired autophagosome–lysosome fusion, implicating autophagy dysfunction in disease pathogenesis (PMID:32185393).

No studies have refuted the CYLD–ALS association, but current evidence is limited to a single kindred. Additional independent cohorts and functional validations are needed to confirm causality. Key take-home: CYLD variant screening may be considered in familial FTD-ALS presentations, but the evidence remains limited.

References

• Brain • 2020 • CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis. PMID:32185393

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