Genetic and immunohistochemical detection of mutations inactivating the keratinocyte transglutaminase in patients with lamellar ichthyosis

Autosomal recessive lamellar ichthyosis is a clinically heterogeneous group of severe congenital keratinization disorders that is characterized by generalized hyperkeratosis and variable erythema. About half of the patients have mutations in the TGM1 gene, which encodes the keratinocyte transglutaminase. Linkage studies have shown that at least two further loci for autosomal recessive lamellar ichthyosis must exist. We present here two patients with lamellar ichthyosis caused by mutations in the TGM1 gene. The first patient is compound heterozygous for the novel missense mutation C53S and the splice mutation A3447G. The second patient, a child of consanguineous parents from Tunisia, is homozygous for the unknown nonsense mutation W263X. This is the first report of a mutation, C53S, that affects the region of the keratinocyte transglutaminase that is essential for anchorage of the enzyme to the plasma membrane. A novel, rapid in situ transglutaminase activity assay revealed the absence of keratinocyte transglutaminase activity in both patients. The mutations described are hence causative for the ichthyosis phenotype.