title: Two novel recessive mutations in KRT14 identified in a cohort of 21 Spanish families with epidermolysis bullosa simplex.
abstract: BACKGROUND
  Basal epidermolysis bullosa simplex (EBS) is a group of blistering genodermatoses mostly caused by mutations in the keratin genes, KRT5 and KRT14. Recessive mutations represent about 5% of all EBS mutations, being common and specific in populations with high consanguinity, where affected patients show severe phenotypes.
  
  
  OBJECTIVE
  To accomplish the first mutational analysis in patients of Spanish origin with EBS and to delineate a comprehensive genotype-phenotype correlation.
  
  
  METHODS
  Twenty-one EBS families were analysed. Immunofluorescence mapping at the dermoepidermal junction level was performed on skin biopsies from patients. Mutation screening of the entire coding sequences of KRT5 and KRT14 in genomic DNA was assessed by polymerase chain reaction and direct sequencing.
  
  
  RESULTS
  KRT5 or KRT14 causative mutations were identified in 18 of the 21 EBS families. A total of 14 different mutations were disclosed, of which 12 were dominant missense mutations and two truncating recessive mutations. Five of the 14 mutations were novel including three dominant in KRT5 (p.V186E, p.T321P and p.A428T) and two recessive in KRT14 (p.K116X and p.K250RfsX8). The two patients with EBS carrying homozygous recessive mutations were affected by severe phenotypes and belonged to consanguineous families. All five families with the EBS Dowling-Meara subtype carried recurrent mutations affecting the highly conserved ends of the α-helical rod domain of K5 and K14. The seven mutations associated with the localized EBS subtype were widely distributed along the KRT5 and KRT14 genes. Two families with mottled pigmentation carried the P25L mutation in KRT5, commonly associated with this subtype.
  
  
  CONCLUSIONS
  This study further confirms the genotype-phenotype correlation established for EBS in other ethnic groups, and is the first in a Mediterranean country (excluding Israel). This study adds two novel recessive mutations to the worldwide record to date, which includes a total of 14 mutations. As in previous reports, the recessive mutations resulted in a lack of keratin K14, giving rise to a generalized and severe presentation.
authors.affiliation: Regenerative Medicine Unit, Epithelial Biomedicine Division, Basic Research Department, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Av. Complutense 22, 28040 Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: García
authors.forename: J L
authors.initials: JL
authors.lastname: Santiago
authors.forename: A
authors.initials: A
authors.lastname: Terrón
authors.forename: A
authors.initials: A
authors.lastname: Hernández-Martín
authors.forename: A
authors.initials: A
authors.lastname: Vicente
authors.forename: C
authors.initials: C
authors.lastname: Fortuny
authors.forename: R
authors.initials: R
authors.lastname: De Lucas
authors.forename: J C
authors.initials: JC
authors.lastname: López
authors.forename: N
authors.initials: N
authors.lastname: Cuadrado-Corrales
authors.forename: A
authors.initials: A
authors.lastname: Holguín
authors.forename: N
authors.initials: N
authors.lastname: Illera
authors.forename: B
authors.initials: B
authors.lastname: Duarte
authors.forename: C
authors.initials: C
authors.lastname: Sánchez-Jimeno
authors.forename: S
authors.initials: S
authors.lastname: Llames
authors.forename: E
authors.initials: E
authors.lastname: García
authors.forename: C
authors.initials: C
authors.lastname: Ayuso
authors.forename: L
authors.initials: L
authors.lastname: Martínez-Santamaría
authors.forename: D
authors.initials: D
authors.lastname: Castiglia
authors.forename: N
authors.initials: N
authors.lastname: De Luca
authors.forename: A
authors.initials: A
authors.lastname: Torrelo
authors.forename: D
authors.initials: D
authors.lastname: Mechan
authors.forename: D
authors.initials: D
authors.lastname: Baty
authors.forename: G
authors.initials: G
authors.lastname: Zambruno
authors.forename: M J
authors.initials: MJ
authors.lastname: Escámez
authors.forename: M
authors.initials: M
authors.lastname: Del Río
mesh_terms: D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D015331:Cohort Studies; D003241:Consanguinity; D004252:DNA Mutational Analysis; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D053547:Keratin-14 / Q000235:genetics*; D053555:Keratin-5 / Q000235:genetics; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D013030:Spain; D055815:Young Adult
chemical_list: C507540:KRT14 protein, human; C503940:KRT5 protein, human; D053547:Keratin-14; D053555:Keratin-5