Three Novel Point Mutations in the Keratinocyte Transglutaminase (TGK) Gene in Lamellar Ichthyosis: Significance for Mutant Transcript Level, TGK Immunodetection and Activity

Petit, E.; Huber, Marcel; Rochat, Ariane; Bodemer, Christine; Teillac-Hamel, D.; Müh, J.P.; Revuz, J.; Barrandon, Yann; Lathrop, Mark; Prost, Y. De; Hohl, Daniel; Hovnanian, Alain

doi:10.1159/000484767

Cited by 32 publications

(29 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Exon 3 was the most common coding sequence site for mutations, with 30 affected individuals from 23 unrelated ARCI families having TGM1 mutations 5 8 11 15 17 20 23 25 32 57. The most 5′ and 3′ TGM1 mutations occurred in exon 2 (c.125C→A (S42Y))16 and the most 3′ mutation reported occurred in exon 15 (c.2320C→T (Q774X))13…”

Section: Resultsmentioning

confidence: 99%

“…TGase-1 is responsible for catalysing the critical N ϵ -(γ-glutamyl) lysine crosslinking of ARP preserver proteins such as involucrin and loricrin during the formation of the CCE 37 38. Decreased to absent enzyme activity in TGase-1 has been reported in patients with germline mutations in TGM1 6 – 9 14 17 25 32 39 40. Knockout TGM1 mice present at birth with ARCI-like features, including erythematous, tight, translucent skin, reminiscent of a collodion membrane.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA

Farasat

Wei

Herman

et al. 2008

Journal of Medical Genetics

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA

Farasat

Wei

Herman

et al. 2008

Journal of Medical Genetics

View full text Add to dashboard Cite

show abstract

“…It has been identified in ARCI patients from a variety of ethnic and racial backgrounds, including Caucasian Americans, African-Americans, Germans, Norwegians, and Egyptians [Petit et al, 1997; Huber et al, 1997; Hennies et al, 1998a; Hennies et al, 1998b; Pigg et al, 1998; Pigg et al, 2000; Shevchenko et al, 2000; Esposito et al, 2001; Shawky et al, 2004; Oji et al, 2006; Farasat et al, 2008;]. Including this study, 34 % (147/435) of all TGM1 mutated alleles reported to date carry the c.877-2A>G mutation.…”

Section: Tgm1 Mutation Analysesmentioning

confidence: 85%

“…In 1997, Petit and co-workers described a child homozygous for TGM1 mutation V382M and reduced TGase-1 enzyme activity who presented with large brown scales distributed over his thorax and abdomen that spared the limbs [Petit et al 1997]. This clinical variant was referred as ichthyosis with sparing of the limbs.…”

Section: Clinical and Diagnostic Relevancementioning

confidence: 99%

Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: Summary of mutations (including 23 novel) and modeling of TGase-1

et al. 2009

View full text Add to dashboard Cite

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare cornification diseases. Germline mutations in TGM1 are the most common cause of ARCI in the US. TGM1 encodes for the TGase-1 enzyme that functions in the formation of the cornified cell envelope. We review the clinical manifestations as well as the molecular genetics of ARCI. In addition, we characterized 115 TGM1 mutations reported in 234 patients from diverse racial and ethnic backgrounds (Caucasion Americans, Norwegians, Swedish, Finnish, German, Swiss, French, Italian, Dutch, Portuguese, Hispanics, Iranian, Tunisian, Moroccan, Egyptian, Afghani, Hungarian, African-Americans, Korean, Japanese and South African). We report 23 novel mutations: 71 (62%) missense; twenty (17%) nonsense; nine (8%) deletion; eight (7%) splice-site and seven (6%) insertion. The c.877-2A>G was the most commonly reported TGM1 mutation accounting for 34 % (147/435) of all TGM1 mutant alleles reported to date. It had been shown that this mutation is common among North American and Norwegian patients due to a founder effect. Thirty-one percent (36/115) of all mutations and 41% (29/71) of missense mutations occurred in arginine residues in TGase-1. Forty-nine percent (35/71) of missense mutations were within CpG dinucleotides, and 74% (26/35) of these mutations were C> T or G>A transitions. We constructed a model of human TGase-1 and showed that all mutated arginines that reside in the two beta-barrel domains and two (R142 and R143) in the beta-sandwich are located at domain interfaces. In conclusion, this study expands the TGM1 mutation spectrum, summarizes the current knowledge of TGM1 mutations. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of 5′ methylated CpG dinucleotides. Structurally defective or attenuated cornified cell envelop have been shown in epidermal scales and appendages of ARCI patients with TGM1 mutations.

show abstract

“…[2-5], a disease characterized by lack of a normal barrier to dehydration [6]. Further analysis of the promoter may assist in evaluating cases where promoter sequence alterations are suspected to yield defective TGM1 expression [7,8]. …”

Section: Introductionmentioning

confidence: 99%

A distal region of the human TGM1 promoter is required for expression in transgenic mice and cultured keratinocytes

Phillips

Jessen

et al. 2004

BMC Dermatol

View full text Add to dashboard Cite

BackgroundTGM1(transglutaminase 1) is an enzyme that crosslinks the cornified envelope of mature keratinocytes. Appropriate expression of the TGM1 gene is crucial for proper keratinocyte function as inactivating mutations lead to the debilitating skin disease, lamellar ichthyosis. TGM1 is also expressed in squamous metaplasia, a consequence in some epithelia of vitamin A deficiency or toxic insult that can lead to neoplasia. An understanding of the regulation of this gene in normal and abnormal differentiation states may contribute to better disease diagnosis and treatment.MethodsIn vivo requirements for expression of the TGM1 gene were studied by fusing various lengths of promoter DNA to a reporter and injecting the DNA into mouse embryos to generate transgenic animals. Expression of the reporter was ascertained by Western blotting and immunohistochemistry. Further delineation of a transcriptionally important distal region was determined by transfections of progressively shortened or mutated promoter DNA into cultured keratinocytes.ResultsIn vivo analysis of a reporter transgene driven by the TGM1 promoter revealed that 1.6 kilobases, but not 1.1 kilobases, of DNA was sufficient to confer tissue-specific and cell layer-specific expression. This same region was responsible for reporter expression in tissues undergoing squamous metaplasia as a response to vitamin A deprivation. Mutation of a distal promoter AP1 site or proximal promoter CRE site, both identified as important transcriptional elements in transfection assays, did not prevent appropriate expression. Further searching for transcriptional elements using electrophoretic mobility shift (EMSA) and transfection assays in cultured keratinocytes identified two Sp1 elements in a transcriptionally active region between -1.6 and -1.4 kilobases. While mutation of either Sp1 site or the AP1 site singly had only a small effect, mutation of all three sites eliminated nearly all the transcriptional activity.ConclusionsA distal region of the TGM1 gene promoter, containing AP1 and Sp1 binding sites, is evolutionarily conserved and responsible for high level expression in transgenic mice and in transfected keratinocyte cultures.

show abstract

Three Novel Point Mutations in the Keratinocyte Transglutaminase (TGK) Gene in Lamellar Ichthyosis: Significance for Mutant Transcript Level, TGK Immunodetection and Activity

Cited by 32 publications

References 16 publications

Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA

Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA

Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: Summary of mutations (including 23 novel) and modeling of TGase-1

A distal region of the human TGM1 promoter is required for expression in transgenic mice and cultured keratinocytes

Contact Info

Product

Resources

About