TGM5

TGM5 encodes transglutaminase 5 (TG5), a calcium-dependent enzyme strongly expressed in epidermal granular cells that catalyzes protein cross-linking of structural substrates—including keratins 1 and 10, involucrin, loricrin, and corneodesmosin—during terminal differentiation to form the cornified cell envelope (PMID:16380904, PMID:22622422). Loss-of-function mutations in TGM5, such as the recurrent G113C missense change that completely abolishes enzymatic activity in vitro, cause acral peeling skin syndrome (APSS) by disrupting cell–cell adhesion between the stratum granulosum and stratum corneum (PMID:16380904, PMID:25644735). In APSS keratinocytes, compensatory upregulation of cornified envelope components occurs in response to TG5 deficiency, indicating a feedback mechanism for epidermal barrier stabilization (PMID:22622422).

1. 2005 High

   The central question of whether TG5 enzymatic cross-linking activity is essential for epidermal cohesion was answered: the G113C mutation abolishes TG5 activity in vitro, establishing a direct causal link between TGM5 loss-of-function and acral peeling skin syndrome.

   Evidence In vitro biochemical cross-linking assay, 3D structural modeling, and homozygosity mapping in APSS families

   PMID:16380904

   Open questions at the time

   • No in vivo animal model to confirm epidermal barrier defect is cell-autonomous
   • Structural basis of catalytic inactivation by G113C not resolved at atomic resolution
   • Relative contribution of TG5 versus other transglutaminases (TG1, TG3) to cornified envelope formation not delineated
2. 2012 High

   The downstream consequences of TG5 deficiency in patient skin were characterized: multiple TGM5 mutations alter the expression and distribution of key differentiation markers (K1, K10, involucrin, loricrin, corneodesmosin), revealing compensatory upregulation that partially stabilizes the barrier.

   Evidence qPCR, immunoblotting, immunofluorescence, and transglutaminase activity assay in APSS patient keratinocytes and skin biopsies

   PMID:22622422

   Open questions at the time

   • Whether compensatory upregulation is transcriptionally driven or reflects post-translational stabilization is unclear
   • Which specific cross-linked products are missing in TG5-deficient cornified envelopes has not been mapped
3. 2015 Medium

   The allelic spectrum of pathogenic TGM5 variants was expanded with splice-site and missense mutations confirmed to abolish TG5 activity, reinforcing that catalytic loss is the unifying pathogenic mechanism.

   Evidence Transglutaminase activity assay and RT-PCR for aberrant splicing in patient samples

   PMID:25644735

   Open questions at the time

   • Single study; independent replication of specific splice-site consequences not yet reported
   • Quantitative relationship between residual TG5 activity and disease severity not established

• The specific cross-linked protein products generated by TG5 in vivo, the structural determinants of substrate selectivity, and the functional interplay with TG1 and TG3 in cornified envelope assembly remain unresolved.
• No crystal structure or cryo-EM structure of TG5 available
• No Tgm5-knockout mouse model reported
• Genotype–phenotype correlation across the full mutation spectrum is incomplete