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Keratin 71 Mutations: From Water Dogs to Woolly Hair

2012; Elsevier BV; Volume: 132; Issue: 10 Linguagem: Inglês

10.1038/jid.2012.291

1523-1747

Sivan Harel, Angela M. Christiano,

Wnt/β-catenin signaling in development and cancer

The study of rare genetic disorders of the hair follicle has resulted in the identification of many causative genes, leading to the potential for the development of novel therapeutic approaches for both inherited and acquired hair disorders. In this issue, Fujimoto et al., 2012Fujimoto A. Inoue A. Ohyama M. et al.A missense mutation within the helix initiation motif of the keratin 71 (KRT71) gene underlies autosomal dominant woolly hair/hypotrichosis.J Invest Dermatol. 2012; 132: 2342-2349Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar identify a missense mutation within the keratin 71 (KRT71) gene as the cause for autosomal dominant woolly hair/hypotrichosis in a Japanese family. This represents the first human mutation in KRT71 to be linked to a hair disorder, establishing this gene as an important determinant of mammalian hair texture. Moreover, this finding provides new insight into the relationship between similar phenotypes resulting from mutations in distinct regulatory pathways and underscores the role of the inner root sheath in human hair growth. The study of rare genetic disorders of the hair follicle has resulted in the identification of many causative genes, leading to the potential for the development of novel therapeutic approaches for both inherited and acquired hair disorders. In this issue, Fujimoto et al., 2012Fujimoto A. Inoue A. Ohyama M. et al.A missense mutation within the helix initiation motif of the keratin 71 (KRT71) gene underlies autosomal dominant woolly hair/hypotrichosis.J Invest Dermatol. 2012; 132: 2342-2349Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar identify a missense mutation within the keratin 71 (KRT71) gene as the cause for autosomal dominant woolly hair/hypotrichosis in a Japanese family. This represents the first human mutation in KRT71 to be linked to a hair disorder, establishing this gene as an important determinant of mammalian hair texture. Moreover, this finding provides new insight into the relationship between similar phenotypes resulting from mutations in distinct regulatory pathways and underscores the role of the inner root sheath in human hair growth. Along with the sebaceous gland, the sweat gland and the arrector pili muscle, the hair follicle constitutes the pilosebaceous unit, a complex appendage of the skin. Featuring a highly organized structure, the hair follicle is composed of multiple epithelial layers, creating concentric circles of differentiated cell types. The highly keratinized hair shaft at the center of this cylinder consists of three layers of cells: the medulla, cortex, and cuticle. It is surrounded by the inner root sheath (IRS), composed of the Henle's, Huxley's, and IRS cuticle layers. The IRS is enclosed by the companion layer and the outer root sheath, which is continuous with the basal layer of the epidermis. The entire epithelial structure is surrounded by the sebaceous gland, which secretes lipids into the hair canal (Langbein and Schweizer, 2005Langbein L. Schweizer J. Keratins of the human hair follicle.Int Rev Cytol. 2005; 243: 1-78Crossref PubMed Scopus (199) Google Scholar). Development of the hair follicle occurs during embryogenesis and involves three main steps: hair follicle induction, organogenesis, and differentiation. Remarkably, this developmental program is repeated to a certain extent throughout adult life, as the hair follicle undergoes phases of growth and regression. Reciprocal and coordinated signals between epithelial and mesenchymal stem cells lead to the differentiation of proliferating matrix cells in the anagen hair bulb along the lineages of the IRS and the hair shaft (Fuchs, 2007Fuchs E. Scratching the surface of skin development.Nature. 2007; 445: 834-842Crossref PubMed Scopus (644) Google Scholar). Keratin proteins have an important role in the mechanical support of hair development. These evolutionarily conserved proteins are classified into type I (acidic) and type II (neutral basic) based on their gene structure, chromosomal location, and ability to form obligate heterodimers with the other keratin type. Acidic and basic keratins bind each other to generate the intermediate filaments, which provide the hair follicle with its structural integrity. All keratin proteins share a structural organization composed of the N-terminal head domain, a central rod domain, and the C-terminal tail domain. Specifically, the N and C termini of the central α-helix contain helix initiation motif and helix termination motif, respectively, which are essential for dimerization of type I and type II keratins (Coulombe and Omary, 2002Coulombe P.A. Omary M.B. "Hard" and "soft" principles defining the structure, function and regulation of keratin intermediate filaments.Curr Opin Cell Biol. 2002; 14: 110-122Crossref PubMed Scopus (557) Google Scholar). About half of the keratins are restricted to various compartments of the hair follicle. Hair keratins, in contrast to epithelial keratins, possess a highly sulfur-rich head and tail domain responsible for the tough, filamentous structure of the hair and nails (Langbein et al., 1999Langbein L. Rogers M.A. Winter H. et al.The catalog of human hair keratins.Biochemistry. 1999; 274: 19874-19884Google Scholar; Schweizer et al., 2006Schweizer J. Bowden P.E. Pa Coulombe et al.New consensus nomenclature for mammalian keratins.J Cell Biol. 2006; 174: 169-174Crossref PubMed Scopus (520) Google Scholar). Mutations in genes encoding keratins, desmosomes, and lipids signaling lead to a variety of hair disorders, highlighting the important role these proteins have in hair follicle development. Monilethrix, a nonsyndromic hair disorder diagnosed by period changes in hair shaft diameter ("beaded hair"), is characterized by fragile scalp hair and nail abnormalities. The autosomal dominant form of this disease is caused by mutations in KRT81, KRT83, and KRT86, all of which are expressed in the hair cortex (Winter et al., 1997Winter H. Rogers M.A. Langbein L. et al.Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.Nat Genet. 1997; 16: 372-374Crossref PubMed Scopus (159) Google Scholar; van Steensel et al., 2005van Steensel M. Steijlen P.M. Bladergroen R.S. et al.A missense mutation in the type II hair keratin hHb3 is associated with monilethrix.J Med Genet. 2005; 42: e19Crossref PubMed Scopus (64) Google Scholar). Autosomal recessive pure hair and nail ectodermal dyplasia, a disorder manifested as complete alopecia and nail dystrophy, is linked to mutations in KRT85. The KRT85 protein is abundantly expressed in the matrix, precortex, and cuticle of the hair shaft (Naeem et al., 2006Naeem M. Jelani M. Lee K. et al.Ectodermal dysplasia of hair and nail type: mapping of a novel locus to chromosome 17p12-q21.2.Br J Dermatol. 2006; 155: 1184-1190Crossref PubMed Scopus (20) Google Scholar; Shimomura et al., 2010bShimomura Y. Wajid M. Kurban M. et al.Mutations in the keratin 85 (KRT85/hHb5) gene underlie pure hair and nail ectodermal dysplasia.J Invest Dermatol. 2010; 130: 892-895Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Mutations in desmoglein 4, the predominant desmoglein of the hair follicle, cause localized autosomal recessive hypotrichosis (Kljuic et al., 2003Kljuic A. Bazzi H. Sundberg J.P. et al.Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris.Cell. 2003; 113: 249-260Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). In addition, some patients with mutations in DSG4 display beaded hair morphology, suggesting that mutations in the gene account for a recessive form of Monilethrix (Schaffer et al., 2006Schaffer J.V. Bazzi H. Vitebsky A. et al.Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions.J Invest Dermatol. 2006; 126: 1286-1291Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar; Shimomura et al., 2006Shimomura Y. Sakamoto F. Kariya N. et al.Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis.J Invest Dermatol. 2006; 126: 1281-1285Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). KRT75 is specifically expressed in the companion layer of the hair follicle. Mutations in KRT75 predispose to the common hair disorder characterized by ingrown beard hairs with inflammation (Winter et al., 2004Winter H. Schissel D. Parry D.A. et al.An unusual Ala12Thr polymorphism in the 1A alpha-helical segment of the companion layer-specific keratin K6hf: evidence for a risk factor in the etiology of the common hair disorder pseudofolliculitis barbae.J Invest Dermatol. 2004; 122: 652-657Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar) and to loose anagen syndrome (Chapalain et al., 2002Chapalain V. Winter H. Langbein L. et al.Is the loose anagen hair syndrome a keratin disorder? A clinical and molecular study.Arch Dermatol. 2002; 138: 501-506Crossref PubMed Google Scholar). The IRS is a critical structural element for supporting and molding the hair shaft. Heterozygous, nonsense mutations in CDSN (corneodesmosin), expressed in the IRS (Mils et al., 1992Mils V. Vincent C. Croute F. et al.The expression of desmosomal and corneodesmosomal antigen shows specific variations during the terminal differentiation of epidermal and hair follicle epithelia.J Histochem Cytochem. 1992; 40: 1329-1337Crossref PubMed Scopus (49) Google Scholar), cause hereditary hypotrichosis simplex restricted to the scalp. Patients with this disorder display disruption of the IRS and aggregates of abnormal CDSN around the hair follicle and the papillary dermis, implying that the mutant CDSN protein is acting in a dominant negative manner (Levy-Nissenbaum et al., 2003Levy-Nissenbaum E. Betz R.C. Frydman M. et al.Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin.Nat Genet. 2003; 34: 151-153Crossref PubMed Scopus (143) Google Scholar). Nonsyndromic forms of hereditary woolly hair (WH) are hair shaft anomalies characterized by tightly curled, slow growing hair, and they are sometimes associated with sparse or depigmented hair. WH can show either as autosomal dominant (ADWH) or autosomal recessive (ARWH). Dominant forms of WH have been linked to mutations in the helix initiation motif of KRT74. KRT74 is a type II keratin highly expressed in the Huxley's layer of the IRS. KRT74 mutations have been shown to interfere with the proper formation of intermediate filaments, resulting in collapse of the hair follicle (Shimomura et al., 2010cShimomura Y. Wajid M. Petukhova L. et al.Autosomal-dominant woolly hair resulting from disruption of keratin 74 (KRT74), a potential determinant of human hair texture.Am J Hum Genet. 2010; 86: 632-638Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). Recessive forms of WH, whose features slowed or arrested hair growth resulting in shortened hair shaft length, have been linked to the PA-PLA1α/LPA/LPA6 signaling pathway. Mutations in two components of this pathway, the LIPH gene (Kazantseva et al., 2006Kazantseva A. Goltsov A. Zinchenko R. et al.Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH.Science. 2006; 314: 982-985Crossref PubMed Scopus (161) Google Scholar) and the LPAR6/P2RY5 gene (Shimomura et al., 2008Shimomura Y. Wajid M. Ishii Y. et al.Disruption of P2RY5, an orphan G protein-coupled receptor, underlies autosomal recessive woolly hair.Nat Genet. 2008; 40: 335-339Crossref PubMed Scopus (176) Google Scholar), both expressed in the IRS of the hair follicle, have been found in patients with ARWH. Mutations in Krt71, known to be expressed throughout the IRS, have been identified in mice, rats, and dogs, and are linked to a wavy-coat phenotype. Krt71 mutant mice ("Caracul mice") display wavy pelage and curvy vibrissae, which are inherited in an autosomal dominant manner (Kikkawa et al., 2003Kikkawa Y. Oyama A. Ishii R. et al.A small deletion hotspot in the type II keratin gene mK6irs1/Krt2-6g on mouse chromosome 15, a candidate for causing the wavy hair of the caracul (Ca) mutation.Genetics. 2003; 165: 721-733PubMed Google Scholar). Rex rats, which possess a Krt71 mutation resulting in the deletion of six amino acids, display curly hair in heterozygous mice and hair loss in homozygous mice (Kuramoto et al., 2010Kuramoto T. Hirano R. Kuwamura M. et al.Identification of the rat Rex mutation as a 7-bp deletion at splicing acceptor site of the Krt71 gene.J Vet Med Sci. 2010; 72: 909-912Crossref PubMed Scopus (22) Google Scholar). Portuguese water dogs were found to display curly versus straight hair, depending on whether they carried a particular allele of Krt71 (Cadieu et al., 2009Cadieu E. Neff M.W. Quignon P. et al.Coat variation in the domestic dog is governed by variants in three genes.Science. 2009; 326: 150-153Crossref PubMed Scopus (233) Google Scholar). However, until now, hair disorders linked to human KRT71 have not been reported. In this issue, Fujimoto et al., 2012Fujimoto A. Inoue A. Ohyama M. et al.A missense mutation within the helix initiation motif of the keratin 71 (KRT71) gene underlies autosomal dominant woolly hair/hypotrichosis.J Invest Dermatol. 2012; 132: 2342-2349Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar describe a mutation within the IRS-specific KRT71 gene in a Japanese family affected with ADWH. To reveal the genetic basis of the disease, the investigators first excluded mutations in genes known to cause WH, such as KRT74, LPAR6, LIPH, and CDSN, as well as in genes involved in other forms of hereditary hypotrichosis, such as APCDD1 (Shimomura et al., 2010aShimomura Y. Agalliu D. Vonica A. et al.APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.Nature. 2010; 464: 1043-1047Crossref PubMed Scopus (181) Google Scholar). On the basis of prior evidence implicating KRT71 in wavy/curly coat in animals, and on the known relationship between genes expressed in the hair follicle IRS and WH phenotypes, the investigators then examined whether mutations in KRT71 are responsible for this phenotype. The K71–K74 gene cluster regulates hair texture across species. The K71–K74 gene cluster regulates hair texture across species. Using direct sequencing, in this issue Fujimoto et al., 2012Fujimoto A. Inoue A. Ohyama M. et al.A missense mutation within the helix initiation motif of the keratin 71 (KRT71) gene underlies autosomal dominant woolly hair/hypotrichosis.J Invest Dermatol. 2012; 132: 2342-2349Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar show that the patients carry a heterozygous nucleotide change in exon 1 of the KRT71 gene, which was predicted to result in substitution of phenylalanine with cysteine within the helix initiation motif of the KRT71 protein. To determine whether this mutation affects KRT71 function, the investigators transfected expression vectors for either wild-type or mutated KRT71 into human cell lines. They showed that the mutation does not affect the expression levels of KRT71, but instead causes severe mislocalization of the protein, resulting in disruption of the keratin intermediate filament network owing to the inability of KRT71 to heterodimerize with KRT14 and KRT18. Although both KRT71 and KRT74 are implicated in WH phenotypes, the Japanese family with KRT71 mutations also displayed defects in facial hair, whereas the previously reported KRT74 mutation carriers showed a phenotype in scalp hair only. The increased severity of this phenotype is likely attributable to the expression of KRT71 in all three layers of the IRS, whereas KRT74 is restricted to Huxley's layer. By conducting immunofluorescence studies on normal human scalp skin, the investigators then examined a possible relationship between the PA-PLA1α/LPA/LPA6 pathway and KRT71. In human hair follicles, KRT71 is expressed in all the three layers of the IRS, and it overlaps with the PA-PLA1α protein. Moreover, a separate study (Inoue et al., 2011Inoue A. Arima N. Ishiguro J. et al.LPA-producing enzyme PA-PLA(1)alpha regulates hair follicle development by modulating EGFR signalling.EMBO J. 2011; 30: 4248-4260Crossref PubMed Scopus (101) Google Scholar) demonstrated that Krt71 expression was significantly reduced in PA-PLA1α knockout mice, which have a wavy-coat phenotype. This suggests that the PA-PLA1α/LPA/LPA6 pathway is involved in regulation of KRT71 expression in the hair follicle. These lines of evidence, together with genetic data from mouse models and canine studies, highlight the importance of KRT71 as well as the KRT71–KRT74 gene cluster in the regulation of hair texture across mammalian species. This study also provides new information on molecular interactions among genes involved in hair-shaft maintenance, allowing for the development of improved diagnosis and treatment. Interestingly, a comparison of people of African and European ancestry, with divergent distribution of hair texture, revealed several single-nucleotide polymorphisms within KRT71 that showed significant differences in allele frequencies (Shimomura et al., 2010cShimomura Y. Wajid M. Petukhova L. et al.Autosomal-dominant woolly hair resulting from disruption of keratin 74 (KRT74), a potential determinant of human hair texture.Am J Hum Genet. 2010; 86: 632-638Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). Further investigation of allelic variations and mutations in these genes will likely elucidate the genetic factors that control the shaping of hair fibers.