The ichq mutant mouse, a model for the human skin disorder harlequin ichthyosis: mapping, keratinocyte culture, and consideration of candidate genes involved in epidermal growth regulation.

[harlequin ichthyosis]

Harlequin ichthyosis (HI ) is a rare and usually fatal scaling skin disorder . The HI mutant mouse (ichq /ichq ) has many similarities to the human disorder and provides an important model to identify candidate genes . In this study , we report refined mapping of the mouse ichq locus and consideration of the candidate genes : calpain 1 (Capn 1 ), phospholipase C beta 3 (Plcb 3 ), and Rela and Ikka /Chuk that encode components of the nuclear factor -kappa B (NF-kappaB ) pathway . Each are strong candidates because of epidermal expression and /or changes in expression in human HI . All candidates are linked to the ichq locus on mouse Chromosome 19 , although Ikka is located more distally . Genetic mapping in mouse has narrowed the ichq critical region to 4 cM . Keratinocytes from skin of +/+, +/ichq and ichq /ichq mice were cultured ; all genotypes had similar expression of epidermal differentiation markers . RT-PCR amplification and sequence analysis of each candidate gene did not reveal any mutations in the ichq mouse . Mutational screening of CAPN 1 cDNA from different human HI cases revealed a R 433 P change , but analysis of 50 normal samples demonstrated that this was an apparent polymorphism . Sequence of RELA in five unrelated human HI cases was normal . The results provide compelling evidence that none of these genes are the primary defect in the ichq mouse and that CAPN 1 and RELA are not mutated in the human disorder .