TUBB4A – Torsion dystonia type 4

TUBB4A has been implicated in autosomal dominant torsion dystonia type 4 based on heterozygous missense variants reported in unrelated individuals. A c.4C>G (p.Arg2Gly) variant was identified in a patient with isolated cervical dystonia (PMID:28655586), and a c.286G>A (p.Gly96Arg) change was observed in an adult with intermediate dystonia-leukodystrophy features (PMID:28791129). Across these two probands, no familial segregation data are available, consistent with de novo or sporadic presentations.

Functional assays demonstrate that the p.Arg2Gly DYT4 mutation selectively impairs neuronal morphology without altering oligodendrocyte structure or microtubule polymerization, distinguishing it from hypomyelination-associated variants (PMID:28973395). Additional studies in neurons show that p.Arg2Gly disrupts motor protein binding and mitochondrial transport, supporting a dominant toxic mechanism underlying dystonia (PMID:30079973).

References

• Parkinsonism & related disorders • 2017 • Screening study of TUBB4A in isolated dystonia. PMID:28655586
• Human genome variation • 2017 • A novel TUBB4A mutation G96R identified in a patient with hypomyelinating leukodystrophy onset beyond adolescence. PMID:28791129
• Human molecular genetics • 2017 • TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes. PMID:28973395
• Human mutation • 2018 • Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants. PMID:30079973

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