TGM3 and Uncombable Hair Syndrome

This summary outlines the association between TGM3 and uncombable hair syndrome, an entity characterized by a distinct hair shaft abnormality with a frizzy, unmanageable phenotype. The evidence supports an autosomal recessive mode of inheritance and has been derived from both singular case reports and multi‐patient studies (PMID:36541401).

Evidence from a case report demonstrated uncombable hair syndrome resulting from maternal uniparental disomy, which provided an initial insight into the molecular etiology; although the mutation identified in that report was in PADI3, the study emphasizes the role of genes involved in hair shaft formation including TGM3 (PMID:36541401).

A subsequent multi‐patient study analyzed 11 affected children with biallelic pathogenic variants in hair shaft proteins and confirmed an autosomal recessive inheritance pattern. In this study, genetic analyses revealed that individuals carried homozygous or compound heterozygous mutations in TGM3, among other genes, which unified the clinical presentation with the underlying molecular defect (PMID:27866708).

For TGM3 specifically, a truncating mutation, c.1351C>T (p.Gln451Ter), was identified in affected individuals. This variant, which results in protein truncation, underscores the contribution of loss‐of‐function genetic events to the pathogenesis of uncombable hair syndrome (PMID:27866708).

Functional assays have also been pivotal in support of the association. In vitro studies using electrophoretic mobility shift assays and transient transfection experiments in normal human epidermal keratinocytes have delineated critical promoter elements necessary for TGM3 expression, providing a mechanistic basis for the dysregulated hair shaft formation observed in the syndrome (PMID:15335352).

Integrating the genetic and functional findings, the evidence lends robust support to the role of TGM3 in uncombable hair syndrome. Multiple independent studies documenting autosomal recessive inheritance and consistent functional disruption affirm the clinical utility of including TGM3 assessment in the diagnostic workflow for patients with this hair phenotype.

Key Take‑home sentence: Genetic and functional evidence robustly support TGM3 as causative for uncombable hair syndrome, thereby guiding diagnostic decision‑making and future therapeutic strategies.

References

• American journal of medical genetics. Part A • 2023 • Uncombable hair syndrome due to maternal uniparental disomy of chromosome 1 PMID:36541401
• American journal of human genetics • 2016 • Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome PMID:27866708
• Experimental dermatology • 2004 • Characterization of Ets-binding sequence of human transglutaminase 3 gene promoter PMID:15335352

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