TGM1 – Bathing Suit Ichthyosis

TGM1 encodes keratinocyte transglutaminase-1, essential for cornified envelope assembly. Bathing suit ichthyosis (MONDO:0015085) is a rare autosomal recessive variant of ARCI characterized by brownish, plate-like scaling confined to trunk ‘bathing suit’ areas with sparing of face and extremities.

Biallelic TGM1 variants underlie BSI with 13 probands identified: 10 patients in a phenotyped cohort ([PMID:16968736]), one Tunisian child ([PMID:25209454]), and two Burmese siblings ([PMID:31631373]). Segregation in families and compound heterozygosity confirm autosomal recessive transmission. Missense mutations cluster in the catalytic core; a representative allele c.827A>G (p.Tyr276Cys) exhibits impaired thermal stability.

Functional assays on BSI skin demonstrate markedly reduced TGase-1 activity at physiological temperature with near-normal activity at lower temperatures, correlating with warmer-site scaling ([PMID:16968736]). Digital thermography validated topographical scaling by mapping warmer areas. Structural modeling of p.Tyr276Asn and other alleles confirms disruption of the enzyme’s hydrophobic interior and thermal lability.

Mechanistically, BSI results from temperature-sensitive TGase-1 deficiency rather than haploinsufficiency. Enzymatic rescue in vitro by lowering assay temperature supports a conformational instability model. There is no evidence of dominant-negative effects; phenotypic variability suggests additional genetic or environmental modifiers.

While the evidence meets ClinGen Strong for gene–disease association and genetic evidence, and Moderate for functional evidence, further longitudinal studies could refine genotype–phenotype correlations. Genetic testing of TGM1 in suspected BSI cases is critical for accurate diagnosis, prognostication, and potential future temperature-modulated therapies.

Key Take-home: TGM1 pathogenic variants cause a temperature-sensitive autosomal recessive ichthyosis confined to bathing suit areas, and targeted genetic testing enables precise diagnosis and management.

References

• International journal of dermatology | 2014 | Bathing suit ichthyosis caused by a TGM1 mutation in a Tunisian child. PMID:25209454
• Pediatric dermatology | 2020 | Bathing suit ichthyosis: Two Burmese siblings and a review of the literature. PMID:31631373
• Human molecular genetics | 2006 | Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype. PMID:16968736

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