In 4 families with autosomal dominant inheritance of ichthyosis bullosa of Siemens (146800) and in 1 sporadic case of this disorder, Rothnagel et al. (1994) found a G-to-A transition at nucleotide 1510 resulting in a lysine for glutamic acid substitution at residue 117 of the KRT2 protein. Thus in a total of 6 instances, the mutation occurred in the same codon, GAG (glu); the mutation was to GAT in 1 family and to AAG in the 5 others. (According to Rothnagel et al. (1994), the residue designated 117 corresponds to codon 493 of the published sequence.)
In 2 unrelated British families with ichthyosis bullosa of Siemens, McLean et al. (1994) found a glu493-to-lys mutation in the highly conserved LLEGEE helix termination motif, producing a change to LLEGKE. The mutation was predicted to be highly detrimental to keratin filament assembly and/or functional integrity. A G-to-A transition at nucleotide 1510 of the cDNA sequence occurred in a CpG dinucleotide.
Kremer et al. (1994) identified the E493K mutation in a family described as having ichthyosis exfoliativa (see 146800), originally reported by Vakilzadeh and Kolde (1991), and in yet another Dutch family with ichthyosis bullosa of Siemens.
In a large family with ichthyosis bullosa of Siemens in 8 members spanning 3 generations, Basarab et al. (1999) identified the E493K mutation in the KRT2 gene. The patients showed blistering, superficial peeling of the skin, and localized lichenified hyperkeratosis, mainly confined to the limbs. Phenotypic variation with some individuals exhibiting unusual clinical features was also observed. The index patient was erythrodermic at birth and subsequently developed a widespread pustular eruption. She also had hypertrichosis of the limbs, as did an affected female first cousin. Basarab et al. (1999) found that E493K is by far the most frequent mutation in this disorder.
