Mutations of Keratinocyte Transglutaminase in Lamellar Ichthyosis

Abstract

Lamellar ichthyosis is a severe congenital skin disorder characterized by generalized large scales and variable redness. Affected individuals in three families exhibited drastically reduced keratinocyte transglutaminase (TGK) activity. In two of these families, expression of TGK transcripts was diminished or abnormal and no TGK protein was detected. Homozygous or compound heterozygous mutations of the TGK gene were identified in all families. These data suggest that defects in TGK cause lamellar ichthyosis and that intact cross-linkage of cornified cell envelopes is required for epidermal tissue homeostasis.

Consequences of Seven Novel Mutations on the Expression and Structure of Keratinocyte Transglutaminase

“…Membranes were hybridized with 32 P-labeled TGK probes (DH42, 3Ј NC) and involucrin (33,42). Final washes were performed in 0.2 ϫ SSC, 0.1% SDS at 65°C for 30 min.…”

“…DNA Sequencing and Family Analysis of Mutations-The 15 exons of the TGK gene were amplified by PCR as described (33). Forward primers were biotinylated.…”

“…By electron microscopy, five types of lamellar ichthyosis (ichthyosis congenita type I-V) have been distinguished (30). Deleterious mutations in the TGK gene have been reported in lamellar ichthyosis patients providing compelling evidence for the importance of the cornified cell envelope for epidermal homeostasis and the barrier function of the skin (31)(32)(33). However, biochemical data clearly showed that about 50 -60% of LI patients have normal TG activity (34).…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…Mutations in 6 genes have been described in non-HI ARCI to date, including TGM, the gene encoding transglutaminase (TGase)-1, 22,23 the genes ABCA12, 17 NIPAL4 (also known as ICHTHYIN ), 24 CYP4F22, 25 and the lipoxygenase genes ALOX12B and ALOXE3. 26 A large cohort of 520 affected families showed a mutation distribution of 32% for TGM1, 16% for NIPAL4, 12% for ALOX12B, 8% for CYP4F22, 5% for ALOXE3, and 5% for ABCA12, 27 which approximately correlated with a recent report of 250 patients.…”

Polymorphism of transglutaminase 2: unusually low frequency of genomic variants with deficient functions

“…The inherited rare genetic variations (most often SNPs) in the Mendelian disorder genes result in defective proteins leading to severe pathologic conditions in either their homo-or heterozygous forms. Examples in the transglutaminase protein family include the life threatening bleeding syndrome as a consequence of any of the more than 70 reported disease causing mutations of FXIIIa (Duckert et al 1960;Karimi et al 2009) and lamellar ichtiosis in cases of TGM1 mutations (Huber et al 1995). No such genetic mutation of TG2 has been reported so far.…”