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TUB encodes a transcription factor predominantly expressed in neuronal cells and implicated in central nervous system pathways, including neurotransmitter production and thyroid hormone signaling. Essential tremor is the most common adult-onset movement disorder characterized by postural and kinetic tremor of the upper limbs. Here, we review evidence supporting an association between TUB and essential tremor.
In a large autosomal dominant pedigree, whole exome sequencing of 10 affected and 6 unaffected family members identified heterozygous segregation of c.1126G>A (p.Val376Ile) in TUB ([PMID:32956375]). Subsequent targeted re-sequencing in 820 unrelated ET probands versus 630 controls revealed a significant burden of rare nonsynonymous TUB variants (e.g. p.Val376Ile, p.Ile20Phe, p.Arg49Gln) in cases (SKAT-O p = 6.20×10⁻⁸) ([PMID:32956375]).
The mode of inheritance is autosomal dominant with full co-segregation of c.1126G>A (p.Val376Ile) in 10 affected relatives and absence in unaffected family members. The case-control cohort identified only rare missense alleles (MAF < 0.01) without evidence of recurrent or founder variants outside this family.
Functional data include GFP-tagged expression and immunohistochemical studies demonstrating both nuclear and cytoplasmic localization of human TUB isoforms in neuronal cells ([PMID:11000483]). ChIP-seq analyses in mouse brain regions further show that TUB directly regulates genes involved in neurotransmitter biosynthesis and thyroid hormone signaling, congruent with ET pathophysiology ([PMID:32956375]).
No conflicting studies have been reported to dispute the role of TUB in essential tremor. Additional replication in independent families and functional modeling in tremor assays would further substantiate pathogenicity.
Overall, the concordant genetic segregation and case-control enrichment, together with supportive functional evidence, yield a Moderate clinical validity for TUB in autosomal dominant essential tremor. Key take-home: Rare heterozygous TUB variants confer increased risk for essential tremor and warrant inclusion in diagnostic tremor gene panels.
Gene–Disease AssociationModerateSegregation of c.1126G>A (p.Val376Ile) in 10 affected family members consistent with autosomal dominant inheritance and significant burden of rare TUB variants in 820 ET cases vs 630 controls (SKAT-O p=6.20×10⁻⁸) ([PMID:32956375]) Genetic EvidenceModerateEvidence includes segregation in a multiplex family (n=10) and case-control enrichment in 820 probands vs 630 controls (p=6.20×10⁻⁸) ([PMID:32956375]) Functional EvidenceLimitedGFP-tag and immunohistochemistry demonstrate TUB localization in neuronal nuclei and cytoplasm, and ChIP-seq identifies regulation of neurotransmitter and thyroid hormone pathways ([PMID:11000483], [PMID:32956375]) |