TGM5 Mutations Impact Epidermal Differentiation in Acral Peeling Skin Syndrome

Abstract

Acral peeling skin syndrome (APSS) is an autosomal recessive skin disorder characterized by acral blistering and peeling of the outermost layers of the epidermis. It is caused by mutations in the gene for transglutaminase 5, TGM5. Here, we report on clinical and molecular findings in 11 patients and extend the TGM5 mutation database by four, to our knowledge, previously unreported mutations: p.M1T, p.L41P, p.L214CfsX15, and p.S604IfsX9. The recurrent mutation p.G113C was found in 9 patients, but also in 3 of 100 control individuals in a heterozygous state, indicating that APSS might be more widespread than hitherto expected. Using quantitative real-time PCR, immunoblotting, and immunofluorescence analysis, we demonstrate that expression and distribution of several epidermal differentiation markers and corneodesmosin (CDSN) is altered in APSS keratinocytes and skin. Although the expression of transglutaminases 1 and 3 was not changed, we found an upregulation of keratin 1, keratin 10, involucrin, loricrin, and CDSN, probably as compensatory mechanisms for stabilization of the epidermal barrier. Our results give insights into the consequences of TGM5 mutations on terminal epidermal differentiation.

ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phospholipase C γ1 and protein kinase C pathways

“…The CE represents an insoluble protein structure that is stabilized by the cross-linking activity of three epidermal transglutaminases (TGs), namely TG1, TG3 and TG53. However, lack of either TG3 or TG5 activity only leads to minor alterations in CE formation and barrier stability45, while lack of TG1 activity causes severe skin barrier defects. The crucial role of TG1 during CE formation is demonstrated in patients with nonsense or missense mutations in the TGM1 gene, that led to impaired skin barrier formation, transepidermal water loss and skin inflammation in autosomal recessive lamellar ichthyosis or congenital ichthyosiform erythroderma36.…”

Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads

“…The increased labeling of these proteins might be a compensatory mechanism for epidermal barrier disruption. 15 In contrast, the staining of filaggrin in the epidermis of individual 1 (antibody catalog number ab81468, Abcam) and in the epidermis of individual 2 (antibody catalog number NCL-Filaggrin, Leica Biosystems), as well as the staining of the tight junction component claudin-1 16 (antibody catalog number 13255, Cell Signaling Technology) in the epidermis of individual 1 was indistinguishable from control (data not shown).…”

Molecular Heterogeneity of Epidermolysis Bullosa Simplex: Contribution of EXPH5 Mutations

“…However, the disease is genetically heterogeneous with about 25-30% of patients lacking mutations in those genes (Rugg et al, 2007;Bolling et al, 2011;Bruckner-Tuderman and Has, 2012). Well-defined subtypes of EBS are associated with typical clinical features and molecular pathology, but patients with mild skin fragility often exhibit less characteristic features rendering the determination of the candidate gene difficult (Groves et al, 2010;Liu et al, 2012;Pigors et al, 2012;Kiritsi et al, 2013). Recently, a homozygous frameshift mutation in the exophilin-5 gene (EXPH5) was identified in three individuals of a consanguineous Iraqi family with mild skin fragility (McGrath et al, 2012).…”