title: A homozygous missense variant in type I keratin KRT25 causes autosomal recessive woolly hair.
abstract: BACKGROUND
  Woolly hair (WH) is a hair abnormality that is primarily characterised by tightly curled hair with abnormal growth.
  
  
  METHODS
  In two unrelated consanguineous Pakistani families with non-syndromic autosomal recessive (AR) WH, homozygosity mapping and linkage analysis identified a locus within 17q21.1-q22, which contains the type I keratin gene cluster. A DNA sample from an affected individual from each family underwent exome sequencing.
  
  
  RESULTS
  A homozygous missense variant c.950T>C (p.(Leu317Pro)) within KRT25 segregated with ARWH in both families, and has a combined maximum two-point LOD score of 7.9 at ϴ=0. The KRT25 variant is predicted to result in disruption of the second α-helical rod domain and the entire protein structure, thus possibly interfering with heterodimerisation of K25 with type II keratins within the inner root sheath (IRS) of the hair follicle and the medulla of the hair shaft.
  
  
  CONCLUSIONS
  Our findings implicate a novel gene involved in human hair abnormality, and are consistent with the curled, fragile hair found in mice with Krt25 mutations, and further support the role of IRS-specific type I keratins in hair follicle development and maintenance of hair texture.
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan Department of Biochemistry & Molecular Biology, National University of Science & Technology (NUST), Islamabad, Pakistan.
authors.forename: Syed Irfan
authors.initials: SI
authors.lastname: Raza
authors.affiliation: Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.lastname: Irfanullah
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Shamim
authors.initials: S
authors.lastname: Shahi
authors.affiliation: Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Anushree
authors.initials: A
authors.lastname: Acharya
authors.affiliation: Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Dai
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos-Cortez
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.affiliation: Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D006197:Hair / Q000002:abnormalities*; D006201:Hair Diseases / Q000235:genetics*; D006801:Humans; D053530:Keratins, Type I / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010154:Pakistan; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D053530:Keratins, Type I
keywords: K25; KRT25; autosomal recessive woolly hair; inner root sheath; type I keratin gene cluster