A mutation in the hair matrix and cuticle keratin KRTHB5 gene causes ectodermal dysplasia of hair and nail type

Background: Ectodermal dysplasias are developmental disorders affecting tissues of ectodermal origin. To date, four different types of ectodermal dysplasia involving only hair and nails have been described. In an effort to understand the molecular bases of this form of ectodermal dysplasia, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. Objective: To identify the gene underlying the phenotype. Methods: Microsatellite markers were genotyped in candidate regions and two point and multipoint parametric linkage analysis carried out. Results: The disease locus was mapped to a 16.6 centimorgan region on chromosome 12q12-q14.1 (Z(max)=8.2), which harbours six type II hair keratin genes. DNA sequence analysis revealed a homozygous missense mutation in the hair matrix and cuticle keratin KRTHB5, leading to histidine substitution of a conserved arginine residue (R78H) located in the head domain. Conclusions: This report provides the first direct evidence relating to the molecular pathogenesis of pure hair-nail ectodermal dysplasias.