TUBB – Multiple benign circumferential skin creases on limbs

Circumferential skin creases Kunze type (CSC-KT; MONDO:0007990) is characterized by excess folding of skin forming ring-like creases on the limbs, often accompanied by facial dysmorphism, growth delay, intellectual disability, microcephaly, cerebral cortical atrophy and corpus callosum hypoplasia. TUBB (HGNC:20778) encodes a β-tubulin isotype highly expressed in developing brain and skin and has been implicated in CSC-KT through heterozygous missense variants in the N-terminal domain.

Genetic evidence for an autosomal dominant mode of inheritance includes three unrelated CSC-KT probands carrying heterozygous missense TUBB mutations: two de novo and one inherited (from an affected mother) in the N-terminal region. One affected first-degree relative segregates with c.218T>C (p.Met73Thr) ([PMID:29427453]), and additional TUBB missense alleles such as c.161C>T (p.Ala54Val) have been identified in an independent cohort ([PMID:26637975]). These three missense variants cluster in the N-terminal domain, support causality, and show absence in population controls.

Functional studies demonstrate that these TUBB mutants exert a dominant-negative effect on the chaperone‐mediated heterodimer folding and assembly pathway, resulting in reduced yield of native tubulin heterodimers and compromised microtubule dynamics in vitro ([PMID:26637975]). Patient-derived fibroblasts harboring p.Met73Thr similarly exhibit impaired epidermal growth factor and transferrin vesicular trafficking, reflecting microtubule‐dependent transport defects ([PMID:32085672]).

No reports to date have disputed the TUBB–CSC-KT association. The concordant genetic segregation, recurrence in independent cohorts, and consistent functional defects across assays support a Moderate clinical validity classification.

In summary, heterozygous missense variants in the N-terminal domain of TUBB cause autosomal dominant CSC-KT by perturbing tubulin heterodimer assembly and microtubule stability, leading to the characteristic skin creases and neurological anomalies. Genetic testing of TUBB should be considered in patients presenting with ringed skin creases and associated brain malformations.

References

• American journal of human genetics • 2015 • Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type. PMID:26637975
• Clinical genetics • 2018 • Intrafamiliar clinical variability of circumferential skin creases Kunze type caused by a novel heterozygous mutation of N-terminal TUBB gene. PMID:29427453
• International journal of molecular sciences • 2020 • TUBB Variants Underlying Different Phenotypes Result in Altered Vesicle Trafficking and Microtubule Dynamics. PMID:32085672

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