TGM1 – Lamellar Ichthyosis

TGM1 encodes transglutaminase-1, a calcium-dependent enzyme that cross-links proteins during cornified envelope assembly in terminally differentiating keratinocytes. Lamellar ichthyosis is a severe autosomal recessive congenital ichthyosis characterized by collodion membrane at birth, persistent plate-like scales, ectropion, and hyperkeratosis. Defective TGase-1 activity disrupts the stratum corneum barrier, leading to lifelong scaling and increased risk of dehydration and infection. The inheritance is autosomal recessive, with biallelic TGM1 mutations found in the majority of cases.

Genetic Evidence: Multiple studies have identified homozygous or compound heterozygous TGM1 variants in over 230 patients from more than 30 unrelated families (PMID:7824952; PMID:19241467). Analysis of 104 ARCI patients in the US revealed TGM1 mutations in 57 probands, including missense, nonsense, frameshift, and splice-site changes reaching the ClinGen genetic evidence cap (PMID:18948357). A strong founder effect for the c.877-2A>G splice-site mutation has been documented in Norwegian and American cohorts (PMID:9887377; PMID:10914678).

Variant Spectrum: Over 115 distinct TGM1 variants have been reported, including >70 missense, 20+ nonsense, and numerous small deletions/insertions distributed across the beta-sandwich, catalytic core, and beta-barrel domains. Recurrent hot spots at CpG dinucleotides (e.g., Arg142Cys, Arg396Leu) account for ~30% of all alleles. The frameshift variant c.371del (p.Gln124ArgfsTer16) exemplifies truncating alleles causing loss of TGase-1 activity (PMID:12534611).

Segregation and Carrier Frequency: Segregation of pathogenic TGM1 alleles has been confirmed in multiple consanguineous and outbred families, with an average of two carriers per pedigree and clear cosegregation in affected sibships. A cluster study in Ecuador demonstrated a 78:1000 carrier frequency for c.1187G>A (p.Arg396His) suggestive of a recent founder effect (PMID:31073126).

Functional Evidence: In situ and biochemical assays of patient skin consistently show markedly reduced or absent transglutaminase-1 activity in granular layers (PMID:9261103). Expression of mutant TGase-1 in keratinocyte and insect cell systems reveals impaired proteolytic processing and enzyme activation for variants such as Arg142His and Arg315Leu (PMID:9593710). Structural modeling corroborates destabilizing effects of core-domain missense changes.

Mechanism and Clinical Integration: Pathogenic TGM1 mutations lead to haploinsufficiency or null alleles that abolish cross-linking of the cornified envelope, weakening the epidermal barrier. The genotype correlates with phenotype severity: truncating alleles generally confer more severe hypohidrosis and ectropion. Early molecular diagnosis enables prenatal testing, genetic counseling, and tailored management including keratolytics and retinoid therapy.

Key Take-Home: TGM1 variants cause definitive autosomal recessive lamellar ichthyosis through loss of transglutaminase-1 activity; genetic testing of TGM1 is essential for diagnosis, carrier screening, and guiding early intervention.

References

• Science • 1995 • Mutations of keratinocyte transglutaminase in lamellar ichthyosis. PMID:7824952
• The Journal of biological chemistry • 1997 • Consequences of seven novel mutations on the expression and structure of keratinocyte transglutaminase. PMID:9261103
• The Journal of investigative dermatology • 1998 • Transglutaminase 1 mutations in lamellar ichthyosis. Loss of activity due to failure of activation by proteolytic processing. PMID:9593710
• Journal of medical genetics • 2009 • Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA. PMID:18948357
• 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

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