TARDBP – Amyotrophic Lateral Sclerosis

TAR DNA-binding protein 43 (TDP-43), encoded by TARDBP, is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and harbors pathogenic variants in 1–4% of cases. The clinical validity of the TARDBP–ALS association is Strong based on consistent segregation in multiple kindreds and concordant functional studies.

TARDBP variants cause autosomal dominant ALS. Segregation of pathogenic alleles has been documented in at least 15 affected relatives across unrelated families (PMID:18779421, PMID:20697052). Large cohort screens report over 30 distinct missense changes in both sporadic and familial ALS.

The variant spectrum clusters in the C-terminal glycine-rich domain, including recurrent alleles such as c.1009A>G (p.Met337Val), c.1144G>A (p.Ala382Thr), and c.1042G>T (p.Gly348Cys). The founder p.Ala382Thr allele accounts for ~30% of Sardinian ALS and segregates in multiple pedigrees without occurrence in controls (PMID:20697052).

Functional studies demonstrate that mutant TDP-43 exhibits increased aggregation propensity, cytoplasmic mislocalization, and neurotoxicity. The p.Met337Val mutation accelerates TDP-43 fragmentation and induces neural apoptosis in vivo, while transgenic models recapitulate ALS-like motor deficits (PMID:18309045).

No credible evidence refutes the pathogenic role of TARDBP in ALS; variants are absent from large control databases and co-localize with TDP-43 inclusions in patient tissues.

Collectively, autosomal dominant TARDBP variants are strongly supported as causal in ALS, guiding diagnostic genetic testing and informing therapeutic strategies targeting TDP-43 aggregation.

References

• Archives of neurology | 2008 | Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations PMID:18779421
• Archives of neurology | 2010 | Amyotrophic lateral sclerosis-frontotemporal lobar dementia in 3 families with p.Ala382Thr TARDBP mutations PMID:20697052
• Science | 2008 | TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis PMID:18309045

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