Acral lamellar ichthyosis with amino acid substitution in the C-terminus of keratin 2

Abstract

Background: Most cases of hereditary ichthyoses present with generalized scaling and skin dryness. However, in some cases skin involvement is restricted to particular body regions as in acral lamellar ichthyosis.

Objectives: We report on the genetic basis of acral ichthyosis in two families presenting with a similar phenotype.

Methods: Genetic testing was performed by targeted next generation sequencing and whole-exome sequencing. For identity-by-descent analysis, the parents were genotyped and data analysis was performed with the Chromosome Analysis Suite Software. RT-PCR with RNA extracted from skin samples was used to analyse the effect of variants on splicing.

Results: Genetic testing identified a few heterozygous variants, but only the variant in KRT2 c.1912 T > C, p.Phe638Leu segregated with the disease and remained the strongest candidate. Pairwise identity-by-descent analysis revealed no indication of family relationship. Phenylalanine 638 is the second last amino acid upstream of the termination codon in the tail of K2, and substitution to leucine is predicted as probably damaging. Assessment of the variant is difficult, in part due to the lack of crystal structures of this region.

Conclusions: Altogether, we show that a type of autosomal dominant acral ichthyosis is most probably caused by an amino acid substitution in the C-terminus of keratin 2.