TGM1 – Congenital non-bullous Ichthyosiform Erythroderma

TGM1 encodes transglutaminase-1 (TGase-1), a key enzyme in cornified cell envelope assembly critical for skin barrier function. Biallelic mutations in TGM1 underlie autosomal recessive congenital ichthyoses, including congenital non-bullous ichthyosiform erythroderma (NBCIE) (MONDO:0019306). Clinical hallmarks of NBCIE include fine scaling on an erythematous background with variable erythroderma and collodion membrane at birth.

Genetic evidence supporting a definitive TGM1–NBCIE association includes over 234 unrelated probands with TGM1 mutations ([PMID:19241467]) and recurrent splice-site and missense alleles. The inheritance is autosomal recessive, with compound heterozygous or homozygous variants segregating in affected families. A representative variant, c.790C>T (p.Arg264Trp), has been reported in a Turkish NBCIE patient with parental carrier status ([PMID:38061711]). Additional founder mutations such as c.877-2A>G account for the majority of Norwegian NBCIE alleles ([PMID:9887377]).

The TGM1 variant spectrum comprises >65 missense substitutions predominantly at CpG dinucleotides and >50 protein-truncating alleles including nonsense, frameshift, and splice-site changes. Recurrent alleles (e.g., c.877-2A>G) demonstrate population-specific founder effects, whereas novel variants continue to expand the mutation repertoire across ethnic groups.

Functional assays consistently reveal severely reduced or absent TGase-1 activity in patient epidermis as measured by monodansyl cadaverine incorporation and immunodetection ([PMID:12823447]). Cellular models expressing TGase-1 mutants (e.g., p.Arg142Cys, p.Arg315Pro) display loss of activity and protein instability, confirming haploinsufficiency as the predominant pathogenic mechanism ([PMID:9261103]). Animal and tissue studies demonstrate defective cornified envelope formation concordant with human phenotypes.

No compelling evidence disputes the TGM1–NBCIE link; cases without TGM1 mutations represent <10 % of NBCIE, suggesting genetic heterogeneity. Overall, genetic and functional data meet ClinGen criteria for a Definitive gene-disease association.

Key Take-home: Biallelic TGM1 mutations cause autosomal recessive NBCIE via TGase-1 deficiency, enabling accurate molecular diagnosis and informing therapeutic development.

References

• Human Mutation • 2009 • Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: summary of mutations (including 23 novel) and modeling of TGase-1. PMID:19241467
• Annals of Dermatology • 2023 • Novel Compound Heterozygous Mutations of TGM1 Gene Identified in a Turkish Collodion Baby Diagnosed with Non-Bullous Congenital Ichthyosiform Erythroderma. PMID:38061711
• Experimental Dermatology • 2003 • Identification of two novel nonsense mutations in the transglutaminase 1 gene in a Hungarian patient with congenital ichthyosiform erythroderma. PMID:12823447
• The Journal of Biological Chemistry • 1998 • Consequences of seven novel mutations on the expression and structure of keratinocyte transglutaminase. PMID:9261103
• European Journal of Human Genetics • 1998 • Strong founder effect for a transglutaminase 1 gene mutation in lamellar ichthyosis and congenital ichthyosiform erythroderma from Norway. PMID:9887377

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