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A new pathogenic keratin 5 mutation in a Hindoestan family with localized epidermolysis bullosa simplex

European Journal of Dermatology. Volume 20, Numéro 1, 27-9, January-February 2010, Genes and skin

DOI : 10.1684/ejd.2010.0804

Summary

Auteur(s) : Sophie C Flohil, Maria C Bolling, Kristia A Kooi, Henny H Lemmink, Marcel F Jonkman , Department of Dermatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, the Netherlands, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Illustrations

ARTICLE

Auteur(s) : Sophie C Flohil¹, Maria C Bolling¹, Kristia A Kooi², Henny H Lemmink², Marcel F Jonkman¹

¹Department of Dermatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, the Netherlands
²Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

accepté le 31 Août 2009

Epidermolysis bullosa simplex (EBS) is a blistering genodermatosis that is mainly caused by mutations in either of the genes KRT5 or KRT14 encoding the basal epidermal keratins 5 (K5) and 14 (K14) [1, 2]. EBS due to keratin mutations can be subdivided into: Dowling-Meara (EBS-DM), generalized other (EBS, gen-nDM; formerly known as Koebner), localized (EBS-loc; formerly known as Weber-Cockayne), migratory circinate (EBS-migr), with mottled pigmentation (EBS-MP), and autosomal recessive (EBS-AR) [3]. EBS-DM is the most severe subtype with congenital generalized grouped blisters in a circinate (ring) pattern, and not herpetiform (en bouquet). The former denominator “herpetiformis” in EBS-DM was a misnomer. In EBS, gen-nDM the skin fragility is generalized as well, but is milder and without the characteristic circinate pattern. EBS-loc is the mildest form of EBS with blistering confined to the hands and feet, sometimes resulting in palmoplantar hyperkeratosis [3]. In EBS-loc, blistering usually begins when the child starts to walk although occasionally the onset may be earlier within the neonatal period. Here we describe a novel pathogenic missense mutation in the 1A domain of K5 in a family with early onset EBS-loc.

Case report

The proband, a 32-year-old male, presented with localized blistering (figure 1) after minor friction, mainly affecting the hands and feet. Blistering was present from birth, and warm weather worsened the symptoms. After puberty the number of skin lesions diminished. Plantar skin showed marked diffuse hyperkeratosis, and postinflammatory hyperpigmentation was seen on his shins. Eyes, nails and mucous membranes were normal and blisters healed without scarring. The proband’s parents were unrelated (figure 2). His father (II-1), two uncles (II-3 and II-9) and two cousins (III-13 and III-15) were similarly affected with blistering. The one year old daughter (IV-3) of the proband was born with a blister on her thumb and later developed blisters in her diaper area.

After mechanically trying to induce a blister, histopathological examination demonstrated splitting through the stratum spinosum of the epidermis corresponding with a physiological friction blister. Electron microscopy of the proband’s lesional skin showed no keratin clumping. Genomic DNA was extracted from the proband (III-3), his daughter (IV-3), mother (II-2), father (II-1) and brother (III-2). PCR amplification and subsequent direct sequence analysis of KRT5 and KRT14 was performed [4]. In KRT5 a heterozygous A-to-T substitution was identified at nucleotide 596 (c.596A>T), altering codon 199 of K5 from a lysine to a methionine (KRT5:p.Lys199Met). The mutation was excluded in 100 matched control samples (data not shown). Surprisingly, another heterozygous variation was found in KRT14 (c.88C>T, p.Arg30Cys). Neither substitution has been described thus far. The proband’s affected father (II-1) and daughter (V-I3) were carriers of both variations as well, the proband’s unaffected mother (II-2) and brother (III-2) did not carry either of them.

All initially analysed affected family members were carriers of KRT5:p.Lys199Met and KRT14:p.Arg30Cys, while the unaffected persons were all negative for both variations, which gave the impression that the variations mutually contributed to the EBS phenotype in this family. To verify this, we investigated genomic DNA of other family members (figure 2). This revealed that all affected family members were carriers of the KRT5:p.Lys199Met mutation, but not all of them carried the KRT14:p.Arg30Cys variation as well. Furthermore, five clinically unaffected family members (II-15, II-17, II-21, III-5 and III-6) were carriers of the KRT14:p.Arg30Cys alone. Additionally, no clinical differences were observed between the affected family members carrying both the mutated KRT5 and KRT14 alleles (II-1, III-3 and IV-3) and the affected family members with only the mutated KRT5 allele (II-9, III-13 and III-15), hereby rejecting the bigenic hypothesis that substitution of an arginine for a cysteine at amino acid position 30 of K14 could have a modifying effect on this K5-causing EBS phenotype and rejecting the hypothesis that KRT14:p.Arg30Cys leads to a phenotype on its own.

Discussion

The KRT5:p.Lys199Met missense mutation has not been described previously. Other mutations have been reported altering the same codon 199 of KRT5, p.Lys199Thr and p.Lys199Arg, that both induce a mild EBS-loc phenotype similar to that in our family [5, 6]. Lysine at codon 199 comprises a highly conserved amino acid at the C-terminal part of the α-helical 1A domain of K5 [2]. Furthermore, this mutation fully segregates with the disease phenotype in the family, hereby confirming the clinical diagnosis of EBS in this proband and the pathogenicity of the mutation. The other DNA change, KRT14:p.Arg30Cys, has not been described in the literature. Since KRT14:p.Arg30Cys did not segregate with the condition and did not cause another phenotype in the family members carrying this variation without the KRT5 mutation, this probably represents a non-pathogenic polymorphism. The KRT14 variation also did not modify the phenotypical outcome of the pathogenic KRT5 mutation. Therefore, we concluded that the KRT5:p.Lys199Met mutation is the only pathogenic mutation in this Hindoestan family.

Acknowledgements

No conflict of interest. No financial support.

References

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