TAF15 – Amyotrophic Lateral Sclerosis

TAF15 (TATA-box binding protein-associated factor 15) is a member of the FET family of RNA-binding proteins involved in transcription and splicing regulation. Pathogenic mutations in related FET members FUS and TDP-43 cause familial ALS (FALS), and TAF15 shares a prion-like domain prompting investigation of its role in amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis; TAF15).

1. Clinical Validity Assessment

We classify the TAF15–ALS association as Limited. Four unrelated ALS probands harbor candidate TAF15 variants (3 familial, 1 sporadic) with no reported segregation in affected relatives and moderate functional concordance.

2. Genetic Evidence

Inheritance is autosomal dominant. In a screen of 263 FALS cases, three missense variants (A31T, two R395Q) were identified in index patients but absent in >1,100 controls; none showed segregation with disease in available families (PMID:21438137). In a Chinese cohort of 21 early-onset sporadic ALS probands, a novel TAF15 c.1535G>A (p.Arg512Gln) was detected in one individual and absent in controls (PMID:31788332). No additional affected relatives have been reported.

3. Variant Spectrum

Reported coding change: c.1535G>A (p.Arg512Gln) (PMID:31788332). Other novel variants remain candidate due to lack of segregation or presence in controls.

4. Functional Evidence

Multiple in vitro and in vivo assays demonstrate that ALS-linked TAF15 variants aggregate, mislocalize, and induce neurotoxicity. Yeast and primary spinal neuron cultures show cytoplasmic foci formation and reduced cell viability for mutant TAF15 (PMID:22065782). Drosophila models expressing mutant TAF15 recapitulate motor neuron degeneration with greater severity than wild type. Postmortem spinal cord immunohistochemistry reveals TAF15 mislocalization in ALS cases (PMID:22454397). Oxidative stress studies indicate mutant FET proteins, including TAF15, perturb stress granule dynamics and RNA processing (PMID:26461404).

5. Conflicting Evidence

A D386N substitution and a p.Arg388His variant occur in controls, and two 24-bp deletions in TAF15 did not segregate with disease, weakening pathogenic claims for some alleles (PMID:21438137).

6. Integration & Conclusion

Sparse case-level data (4 probands) and absence of segregation limit genetic evidence. Moderate functional concordance across cellular and animal models supports a mechanistic link via prion-like aggregation and impaired RNA processing. Additional large-scale sequencing with segregation and case–control analyses are required. Key Take-home: TAF15 variants exhibit plausible pathogenic mechanisms but currently lack sufficient genetic evidence for routine diagnostic inclusion.

References

• American journal of medical genetics. Part B, Neuropsychiatric genetics • 2011 • Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis. PMID:21438137
• Aging and disease • 2019 • Genetic Spectrum and Variability in Chinese Patients with Amyotrophic Lateral Sclerosis. PMID:31788332
• Proceedings of the National Academy of Sciences of the United States of America • 2011 • A yeast functional screen predicts new candidate ALS disease genes. PMID:22065782
• Human molecular genetics • 2012 • Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. PMID:22454397
• Free radical biology & medicine • 2014 • Oxidative stress affects FET proteins localization and alternative pre-mRNA processing in cellular models of ALS. PMID:26461404

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