TAF15

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: ClinGen

TAF15 was first reported in relation to autosomal dominant amyotrophic lateral sclerosis (ALS) in 2011 (Couthouis et al., PMID: 22065782). TAF15 encodes the TATA box-binding protein-associated factor 15 protein, which is a member of the FET protein family (consisting of FUS, EWSR1, and TAF15). These proteins bind RNA and have roles in transcription control, RNA processing, and alternative splicing. TAF15 has a similar structure to the RNA binding proteins, FUS and TDP-43. The similarity between these proteins is what drove researchers to further investigate the potential involvement of TAF15 in ALS. Both case-level and experimental data support this gene-disease relationship. Overall, 11 missense variants and one frameshift variant have been reported in TAF15 in 12 probands (both sporadic and familial ALS cases) across six publications (PMID: 22065782, 21438137, 28889094, 31788332, 33276461, 26742954) that are included in this curation. Although there was functional evidence to support the pathogenicity of four of the variants (PMID: 22065782), all four were also found in the gnomAD v2.1.1 non-neuro database, including in elderly individuals. One case-control analysis was also included in the original Couthouis et al. publication (PMID: 22065782), which demonstrated a significantly greater frequency of TAF15 variants in ALS cases (n=735) in comparison to controls (n=1328), although this could not be scored as the cases were already scored as individuals. A second case-control gene-burden analysis of 3093 ALS cases and 8186 controls found a non-significant greater frequency of TAF15 rare variants in the controls in comparison to the ALS case cohort. Experimentally, the gene-disease relationship is supported by evidence suggesting that TAF15 controls the gene expression of many overlapping genes controlled by known ALS-associated protein FUS (PMID: 27378374, 23416048), and limited evidence of a direct interaction between TAF15 and FUS has been described (PMID: 25625564). TAF15 was also shown to be toxic when expressed in yeast and aggregation prone, both of which are characteristic of the ALS-associated proteins TDP-43 and FUS (PMID: 22065782). In ALS motor neurons TAF15 was shown to mislocalize (PMID: 22065782), and when the protein was upregulated in drosophila model systems, the flies exhibited neuron degeneration in the retina, loss of climbing behaviour, and premature death (PMID: 22065782). In summary, there is limited evidence to support this gene-disease relationship. No contradictory evidence was found for this gene-disease relationship, but more evidence is required, particularly in the definition of pathogenic variants within the gene and further functional analysis of the gene-disease relationship. This classification was approved by the ClinGen ALS GCEP on August 26, 2021 (SOP Version 8).