Keratin 71 Mutations: from Water Dogs to Woolly Hair

CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector COMMENTARY See related article on pg 2342 C-terminal tail domain. Specifically, the N and C termini of the central a-helix contain helix initiation motif and Keratin 71 Mutations: From Water helix termination motif, respectively, which are essential for dimerization of Dogs to Woolly Hair type I and type II keratins (Coulombe 1 1,2 and Omary, 2002). About half of Sivan Harel and Angela M. Christiano the keratins are restricted to various compartments of the hair follicle. The study of rare genetic disorders of the hair follicle has resulted in the Hair keratins, in contrast to epithelial identification of many causative genes, leading to the potential for the develop- keratins, possess a highly sulfur-rich ment of novel therapeutic approaches for both inherited and acquired hair head and tail domain responsible for disorders. In this issue, Fujimoto et al. identify a missense mutation within the the tough, filamentous structure of the keratin 71 (KRT71) gene as the cause for autosomal dominant woolly hair/ hair and nails (Langbein et al., 1999; hypotrichosis in a Japanese family. This represents the first human mutation in Schweizer et al., 2006). 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 Structural disorders of the hair follicle in distinct regulatory pathways and underscores the role of the inner root sheath Mutations in genes encoding keratins, in human hair growth. desmosomes, and lipids signaling lead Journal of Investigative Dermatology (2012) 132, 2315–2317. doi:10.1038/jid.2012.291 to a variety of hair disorders, highlight- ing the important role these proteins have in hair follicle development. Mon- ilethrix, a nonsyndromic hair disorder diagnosed by period changes in hair Hair follicle development developmental program is repeated to shaft diameter (‘‘beaded hair’’), is char- Along with the sebaceous gland, the a certain extent throughout adult life, as acterized by fragile scalp hair and nail sweat gland and the arrector pili mus- the hair follicle undergoes phases of abnormalities. The autosomal dominant cle, the hair follicle constitutes the growth and regression. Reciprocal and form of this disease is caused by muta- pilosebaceous unit, a complex appen- coordinated signals between epithelial tions in KRT81, KRT83,andKRT86, dage of the skin. Featuring a highly and mesenchymal stem cells lead to the all of which are expressed in the hair organized structure, the hair follicle is differentiation of proliferating matrix cortex (Winter et al., 1997; van Steensel composed of multiple epithelial layers, cells in the anagen hair bulb along the et al., 2005). Autosomal recessive creating concentric circles of differen- lineages of the IRS and the hair shaft pure hair and nail ectodermal dyplasia, tiated cell types. The highly keratinized (Fuchs, 2007). a disorder manifested as complete hair shaft at the center of this cylinder alopecia and nail dystrophy, is linked consists of three layers of cells: the Hair follicle keratins to mutations in KRT85. The KRT85 medulla, cortex, and cuticle. It is sur- Keratin proteins have an important role protein is abundantly expressed in the rounded by the inner root sheath (IRS), in the mechanical support of hair devel- matrix, precortex, and cuticle of the hair composed of the Henle’s, Huxley’s, and opment. These evolutionarily conserved shaft (Naeem et al., 2006; Shimomura IRS cuticle layers. The IRS is enclosed proteins are classified into type I (acidic) et al., 2010b). Mutations in desmoglein by the companion layer and the outer and type II (neutral basic) based on their 4, the predominant desmoglein of the root sheath, which is continuous with gene structure, chromosomal location, hair follicle, cause localized autosomal the basal layer of the epidermis. The and ability to form obligate heterodi- recessive hypotrichosis (Kljuic et al., entire epithelial structure is surrounded mers with the other keratin type. Acidic 2003). In addition, some patients with by the sebaceous gland, which secretes and basic keratins bind each other to mutations in DSG4 display beaded lipids into the hair canal (Langbein and generate the intermediate filaments, hair morphology, suggesting that Schweizer, 2005). Development of the which provide the hair follicle with mutations in the gene account for a hair follicle occurs during embryo- its structural integrity. All keratin pro- recessive form of Monilethrix (Schaffer genesis and involves three main steps: teins share a structural organization et al., 2006; Shimomura et al., 2006). hair follicle induction, organogenesis, composed of the N-terminal head KRT75 is specifically expressed in the and differentiation. Remarkably, this domain, a central rod domain, and the companion layer of the hair follicle. Mutations in KRT75 predispose to the 1Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, New common hair disorder characterized by 2 York, USA and Department of Genetics and Development, Columbia University, College of Physicians ingrown beard hairs with inflammation and Surgeons, New York, New York, USA (Winter et al., 2004) and to loose Correspondence: Angela M. Christiano, Department of Dermatology, Columbia University, College of Physicians and Surgeons, 1150 St Nicholas Avenue, Room 307, New York 10032, New York, USA. anagen syndrome (Chapalain et al., E-mail: [email protected] 2002). www.jidonline.org 2315 COMMENTARY Disorders of the hair shaft 2010). Portuguese water dogs were phenotype in scalp hair only. The The IRS is a critical structural element found to display curly versus straight increased severity of this phenotype is for supporting and molding the hair hair, depending on whether they likely attributable to the expression of shaft. Heterozygous, nonsense mutations carried a particular allele of Krt71 KRT71 in all three layers of the IRS, in CDSN (corneodesmosin), expressed (Cadieu et al., 2009). However, until whereas KRT74 is restricted to Huxley’s in the IRS (Mils et al., 1992), cause now, hair disorders linked to human layer. By conducting immunofluo- hereditary hypotrichosis simplex res- KRT71 have not been reported. In this rescence studies on normal human tricted to the scalp. Patients with this issue, Fujimoto et al. (2012) describe a scalp skin, the investigators then disorder display disruption of the IRS mutation within the IRS-specific KRT71 examined a possible relationship and aggregates of abnormal CDSN gene in a Japanese family affected with between the PA-PLA1a/LPA/LPA6 path- around the hair follicle and the papil- ADWH. To reveal the genetic basis of way and KRT71. In human hair follicles, lary dermis, implying that the mutant the disease, the investigators first KRT71 is expressed in all the three CDSNproteinisactinginadominant excluded mutations in genes known to layers of the IRS, and it overlaps with negative manner (Levy-Nissenbaum cause WH, such as KRT74, LPAR6, the PA-PLA1a protein. Moreover, a et al., 2003). Nonsyndromic forms of LIPH, and CDSN, as well as in genes separate study (Inoue et al., 2011) hereditary woolly hair (WH) are hair involved in other forms of hereditary demonstrated that Krt71 expression shaft anomalies characterized by hypotrichosis, such as APCDD1 was significantly reduced in PA-PLA1a tightly curled, slow growing hair, and (Shimomura et al., 2010a). On the knockout mice, which have a wavy- they are sometimes associated with basis of prior evidence implicating coat phenotype. This suggests that sparse or depigmented hair. WH can KRT71 in wavy/curly coat in animals, the PA-PLA1a/LPA/LPA6 pathway is show either as autosomal dominant and on the known relationship between involved in regulation of KRT71 expres- (ADWH) or autosomal recessive genes expressed in the hair follicle sion in the hair follicle. (ARWH). Dominant forms of WH have IRS and WH phenotypes, the investi- These lines of evidence, together with been linked to mutations in the helix gators then examined whether muta- genetic data from mouse models and initiation motif of KRT74. KRT74 is a tions in KRT71 are responsible for this canine studies, highlight the importance type II keratin highly expressed in the phenotype. of KRT71 as well as the KRT71–KRT74 Huxley’s layer of the IRS. KRT74 muta- gene cluster in the regulation of hair tions have been shown to interfere with The K71–K74 gene texture across mammalian species. This the proper formation of intermediate study also provides new information on filaments, resulting in collapse of the cluster regulates hair molecular interactions among genes hair follicle (Shimomura et al., 2010c). texture across species. involved in hair-shaft maintenance, Recessive forms of WH, whose features allowing for the development of slowed or arrested hair growth resulting Using direct sequencing, in this issue improved diagnosis and treatment. Inter- in shortened hair shaft length, have Fujimoto et al. (2012) show that the estingly, a comparison of people of been linked to the PA-PLA1a/LPA/LPA6 patients carry a heterozygous nucleo- African and European ancestry, with signaling pathway. Mutations in two tide change in exon 1 of the KRT71 divergent distribution of hair texture, components of this pathway, the LIPH gene, which was predicted to result revealed several single-nucleotide

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