title: Mutation p.Leu128Pro in the 1A domain of K16 causes pachyonychia congenita with focal palmoplantar keratoderma in a Chinese family.
abstract: Pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by hypertrophic nail dystrophy, is classified into two main clinical subtypes: PC-1 and PC-2. PC-1 is associated with mutations in the KRT6A or KRT16 genes, whereas PC-2 is linked to KRT6B or KRT17 mutations. Blood samples were collected from three generations of a new Chinese PC-1 family, including three PC patients and five unaffected family members. A novel missense mutation p.Leu128Pro (c.383T>C) was identified in a highly conserved helix motif in domain 1A of K16. The disease haplotype carried the mutation and cosegregated with the affection status. PolyPhen2 and SIFTS analysis rated the substitution as probably damaging; Swiss-Model analysis indicated that the structure of the mutant protein contained an unnormal α-helix. Overexpression of mutant protein in cultured cells led to abnormal cell morphology.
  
  
  CONCLUSIONS
  The wider spectrum of KRT16 mutations suggests that changes in codons 125, 127, and 132 are most commonly responsible for PC-1 and that proline substitution mutations at codons 127 or 128 may produce more severe disease. This study extends the KRT16 mutation spectrum and adds new information on the clinical and genetic diversity of PC.
authors.affiliation: Department of Medical Genetics, College of Basic Medical Science, Third Military Medical University, Chongqing, China.
authors.forename: Limeng
authors.initials: L
authors.lastname: Dai
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Guo
authors.forename: Yangming
authors.initials: Y
authors.lastname: Huang
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Liyuan
authors.initials: L
authors.lastname: Fu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Xingying
authors.initials: X
authors.lastname: Guan
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liao
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D053536:Keratin-16 / Q000235:genetics*; D015776:Keratoderma, Palmoplantar, Diffuse / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D053549:Pachyonychia Congenita / Q000235:genetics*; D010212:Papilloma / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: C507431:KRT16 protein, human; D053536:Keratin-16