Identification of Novel and Known Mutations in the Genes for Keratin 5 and 14 in Danish Patients with Epidermolysis Bullosa Simplex: Correlation Between Genotype and Phenotype

• Published in: Journal of investigative dermatology Vol. 112; no. 2; pp. 184 - 190
• Main Authors: Sørensen, Charlotte B., Ladekjær-Mikkelsen, Anne-Sofie, Andresen, Brage S., Brandrup, Flemming, Veien, Niels K., Buus, Sanne K., Anton-Lamprecht, Ingrun, Kruse, Torben A., Jensen, Peter K.A., Eiberg, Hans, Bolund, Lars, Gregersen, Niels
• Format: Journal Article
• Language: English
• Published: Danvers, MA Elsevier Inc 01.02.1999; Nature Publishing
• Subjects: avoidance of pseudogene co-amplification; Biological and medical sciences; Bullous diseases of the skin; Denmark; Dermatology; Epidermolysis Bullosa Simplex - genetics; Family Health; Female; founder effect; Genetic Linkage; Genotype; Haplotypes; Humans; Keratin-14; Keratins - genetics; Male; Medical sciences; Mutation; Pedigree; Phenotype; Polymorphism, Genetic; skin disease; Denmark; Europe; founder effect; skin disease; avoidance of pseudogene co-amplification; Bullous dermatosis; Human; Immunopathology; Keratin; Skin disease; Phenotype; Epidermolysis bullosa; Family study; Autoimmune disease; Genotype; Mutation; Genetic disease
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1046/j.1523-1747.1999.00495.x

Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant inherited skin diseases caused by mutations in either the keratin 5 (K5) or the keratin 14 (K14) genes and characterized by development of intraepidermal skin blisters. The three major subtypes of EBS are Weber-Cockayne, Koebner, and Dowling-Meara, of which the Dowling-Meara form is the most severe. We have investigated five large Danish families with EBS and two sporadic patients with the Dowling-Meara form of EBS. In the sporadic Dowling-Meara EBS patients, a novel K14 mutation (N123S) and a previously published K5 mutation (N176S) were identified, respectively. A novel K14 mutation (K116N) was found in three seemingly unrelated families, whereas another family harbored a different novel K14 mutation (L143P). The last family harbored a novel K5 mutation (L325P). The identified mutations were not present in more than 100 normal chromosomes. Six polymorphisms were identified in the K14 gene and their frequencies were determined in normal controls. These polymorphisms were used to show that the K14 K116N mutation was located in chromosomes with the same haplotype in all three families, suggesting a common ancestor. We observed a strict genotype-phenotype correlation in the investigated patients as the same mutation always resulted in a similar phenotype in all individuals with the mutation, but our results also show that it is not possible to predict the EBS phenotype merely by the location (i.e., head, rod, or linker domains) of a mutation. The nature of the amino acid substitution must also be taken into account.