Novel <scp>TGM</scp>5 mutations in acral peeling skin syndrome

Velden, Jaap J A J van der; Geel, Michel van; Nellen, Ruud G. L.; Jonkman, Marcel F.; McGrath, John A.; Nanda, Arti; Sprecher, Eli; Steensel, M.A.M. van; McLean, W. H. Irwin; Cassidy, Andrew J.

doi:10.1111/exd.12650

Cited by 13 publications

(23 citation statements)

References 23 publications

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“…We collected OMIM data for transglutaminase family which is shown in S3 Table . F13a autosomal recessive mutations lead to F13a deficiency [ 60 , 61 , 62 ], TGM1 has disease causing mutations in autosomal recessive congenital ichthyosis [ 63 , 64 ], TGM5 homozygous LOF mutations cause acral peeling skin syndrome [ 65 , 66 , 67 ] and TGM6 mutations are associated with spinocerebellar ataxia 35 [ 68 ]. Data have not been found for inherited disease related to TGM2, TGM3, TGM4, and TGM7 mutations.…”

Section: Resultsmentioning

confidence: 99%

Genomic variants reveal differential evolutionary constraints on human transglutaminases and point towards unrecognized significance of transglutaminase 2

et al. 2017

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Transglutaminases (TGMs) catalyze Ca2+-dependent transamidation of proteins with specified roles in blood clotting (F13a) and in cornification (TGM1, TGM3). The ubiquitous TGM2 has well described enzymatic and non-enzymatic functions but in-spite of numerous studies its physiological function in humans has not been defined. We compared data on non-synonymous single nucleotide variations (nsSNVs) and loss-of-function variants on TGM1-7 and F13a from the Exome aggregation consortium dataset, and used computational and biochemical analysis to reveal the roles of damaging nsSNVs of TGM2. TGM2 and F13a display rarer damaging nsSNV sites than other TGMs and sequence of TGM2, F13a and TGM1 are evolutionary constrained. TGM2 nsSNVs are predicted to destabilize protein structure, influence Ca2+ and GTP regulation, and non-enzymatic interactions, but none coincide with conserved functional sites. We have experimentally characterized six TGM2 allelic variants detected so far in homozygous form, out of which only one, p.Arg222Gln, has decreased activities. Published exome sequencing data from various populations have not uncovered individuals with homozygous loss-of-function variants for TGM2, TGM3 and TGM7. Thus it can be concluded that human transglutaminases differ in harboring damaging variants and TGM2 is under purifying selection suggesting that it may have so far not revealed physiological functions.

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Section: Resultsmentioning

confidence: 99%

Genomic variants reveal differential evolutionary constraints on human transglutaminases and point towards unrecognized significance of transglutaminase 2

et al. 2017

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“…Acral peeling skin syndrome can also be induced by missense mutations in TGase5 [45]. TGase1 deficiency from a mutation in TGM1 (transglutaminase 1) encoding the TGase1 enzyme can cause lamellar ichthyosis, an autosomal recessive congenital ichthyosis [46,47].…”

Section: Cornified Envelopesmentioning

confidence: 99%

Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities

Lee

2020

IJMS

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Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions through vicious cycles make the mechanism complicated in connection with other mechanisms, particularly immunologic responses. In this article, the molecular mechanisms concerning epidermal barrier abnormalities are reviewed in terms of the following categories: epidermal calcium gradients, filaggrin, cornified envelopes, desquamation, and skin lipids. Mechanisms linked to ichthyoses, atopic dermatitis without exacerbation or lesion, and early time of experimental irritation were included. On the other hand, the mechanism associated with epidermal barrier abnormalities resulting from preceding skin disorders was excluded. The molecular mechanism involved in epidermal barrier dysfunction has been mostly episodic. Some mechanisms have been identified in cultured cells or animal models. Nonetheless, research into the relationship between the causative molecules has been gradually increasing. Further evidence-based systematic data of target molecules and their interactions would probably be helpful for a better understanding of the molecular mechanism underlying the dysfunction of the epidermal barrier.may not be the primary events in lesional skin. However, they can play a role in part as primary abnormalities because abnormalities in the epidermal barrier are already present in non-lesional skin of atopic dermatitis [1]. Epidermal trauma from tape stripping or irritant application also leads to initial disruption of the barrier, although the result at certain time points may be combined with compensatory reactions followed by trauma.Causative mechanisms involved in primary epidermal barrier dysfunction might be more valuable for the prevention of skin diseases induced by barrier abnormalities. However, the underlying mechanism has been discussed mainly in connection with immunologic responses, including cytokine production [1,9,10]. Accordingly, this review covers molecular mechanisms of epidermal barrier dysfunction as primary abnormalities by focusing on the causative factors of skin diseases (atopic dermatitis and ichthyoses) and experimental skin conditions (tape stripping and irritant application) associated with skin barrier abnormalities. Molecular Mechanisms Related to Epidermal Barrier DysfunctionFormation and maintenance of skin barrier integrity could be influenced by genetic and environmental factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Mechanisms related to epidermal barrier dysfunction at molecular levels have commonly illustrated filaggrin mutations [3,11]. Regarding the mechanism behind skin barrier integrity, the role of epidermal calcium gradients could be considered based on their influence on keratinocyte proliferation and dif...

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“…[23] TGM5, causes APSS. [7,8,23] The maternal uncle of the proband (individual V-3) was found to carry the TGM5 mutation in a homozygous state and was heterozygous for the ALOXE3 pathogenic variant ( Figure 2B).…”

Section: Mutation Analysismentioning

confidence: 99%

“…[3] Non-syndromic peeling skin syndromes (PSS) result from defective cell-cell adhesion in the upper layers of the epidermis, leading to superficial peeling. [4][5][6] PSS manifesting with peeling localized to the extremities is termed acral PSS (APSS) and usually results from mutations in the TGM5 gene encoding transglutaminase 5 [7,8] (although mutations in the CSTA gene, encoding cystatin A, have also been shown to cause APSS [9,10] ). Generalized PSS can result from pathogenic variants in FLG2, encoding filaggrin 2, [6] or from mutations in CDSN, encoding corneodesmosin, [11] in which case it is usually associated with significant inflammatory manifestations.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis

Mohamad

Nanda²,

Pavlovsky

et al. 2020

Experimental Dermatology

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Autosomal recessive congenital ichthyosis (ARCI) manifests with generalized scaling often associated with generalized erythema. Mutations in at least 13 different genes have been reported to cause ARCI. Acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder manifesting with peeling over the distal limbs and dorsal surfaces of hands and feet. APSS is mostly due to mutations in TGM5, encoding transglutaminase 5. Both ARCI and APSS are fully penetrant genetic traits. Here, we describe a consanguineous family in which one patient with mild ARCI was found to carry a homozygous mutation in ALOXE3 (c.1238G > A; p.Gly413Asp). The patient was also found to carry a known pathogenic homozygous mutation in TGM5 (c.1335G > C; p.Lys445Asn) but did not display acral peeling skin. Her uncle carried the same homozygous mutation in TGM5 but carried the ALOXE3 mutation in a heterozygous state and showed clinical features typical of APSS. Taken collectively, these observations suggested that the ALOXE3 mutation suppresses the clinical expression of the TGM5 variant. We hypothesized that ALOXE3 deficiency may affect the expression of a protein capable of compensating for the lack of TGM5 expression. Downregulation of ALOXE3 in primary human keratinocytes resulted in increased levels of corneodesmosin, which plays a critical role in the maintenance of cell‐cell adhesion in the upper epidermal layers. Accordingly, ectopic corneodesmosin expression rescued the cell‐cell adhesion defect caused by TGM5 deficiency in keratinocytes as ascertained by the dispase dissociation assay. The present data thus provide evidence for phenotypic suppression in a human hereditary skin disorder.

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Novel TGM5 mutations in acral peeling skin syndrome

Cited by 13 publications

References 23 publications

Genomic variants reveal differential evolutionary constraints on human transglutaminases and point towards unrecognized significance of transglutaminase 2

Genomic variants reveal differential evolutionary constraints on human transglutaminases and point towards unrecognized significance of transglutaminase 2

Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities

Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis

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