Strong founder effect for a transglutaminase 1 gene mutation in lamellar ichthyosis and congenital ichthyosiform erythroderma from Norway

Autosomal recessive congenital ichtyosis (ARCI) is a clinically heterogeneo us disorder of keratinisation. it was recently shown that mutations in the transglutaminase I (TGM1) gene may be associated with the clinical subtypes lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythrod erma (CIE). Thirty-six Norwegian families with LI and seven with non-bullou s CIE were studied with microsatellite markers linked to the TGMI gene. One common halpotype for two markers was found on 74% of disease associated ch romosomes. Three individuals homozygous for the common haplotype, two affec ted by LI and one affected by CIE, were analysed for mutations in the TGMI gene. All three patients were found homozygous for a single A to G transiti on located in the canonical splice acceptor site of intron 5. Probands from the remaining 40 families with LI and CIE were screened for this mutation and the A to G transition was found on 61 out of 72 alleles associated with LI and on 9 out of 15 alleles associated with CIE. These findings suggest a single founder mutation for the majority of patients with LI and CIE in N orway. The 2526A-->G mutation results in the insertion of a guanosine at po sition 877 (876insG) in the mature cDNA and the frame shift creates a prema ture termination at codon 293. The mutation was previously observed in one family with a resulting cDNA that included the entire intron 5. These resul ts suggest that the mutation can result in variant transcripts in different individuals.