GENOTYPE PHENOTYPE CORRELATION IN AUTOSOMAL RECESSIVE LAMELLAR ICHTHYOSIS/

Autosomal recessive lamellar ichthyosis is a severe congenital disorde r of keratinization, characterized by variable erythema of the whole b ody surface and by different scaling patterns. Recently, mutations hav e been identified in patients with lamellar ichthyosis in the TGM1 gen e coding for keratinocyte transglutaminase, and a second locus has bee n mapped to chromosome 2. We have now analyzed the genotype/phenotype correlation in a total of 14 families with lamellar ichthyosis. Linkag e analyses using microsatellites in the region of the TGM1 gene confir med genetic heterogeneity. In patients not linked to the TGM1 gene, th e second region identified on chromosome 2 and a further candidate reg ion on chromosome 20 were excluded, confirming as well the existence o f at least three loci for lamellar ichthyosis. Sequence analyses of th e TGM1 gene in families compatible with linkage to this locus revealed seven different missense mutations, five of these unpublished so far, and one splice mutation. No genotype/phenotype correlation for mutati ons in the TGM1 gene was found in this group of patients, which includ ed two unrelated patients homozygous for the same mutation. Similarly, no clear difference in the clinical picture was seen between patients with TGM1 mutations and those unlinked to the TGM1 locus. Comparison of genetic and clinical classifications for patients with lamellar ich thyosis shows no consistency and thus indicates that clinical criteria currently in use cannot discriminate between the molecularly differen t forms of the disease.