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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 71 Mutations: From Water helix termination motif, respectively, which are essential for dimerization of Dogs to Woolly Hair type I and type II (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 , 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) 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 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 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).

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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 (), 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 poly- gene (Kazantseva et al., 2006) and the in substitution of phenylalanine with morphisms within KRT71 that showed LPAR6/P2RY5 gene (Shimomura et al., cysteine within the helix initiation significant differences in allele frequen- 2008), both expressed in the IRS of the motif of the KRT71 protein. To deter- cies (Shimomura et al., 2010c). Further hair follicle, have been found in patients mine whether this mutation affects investigation of allelic variations and with ARWH. KRT71 function, the investigators trans- mutations in these genes will likely fected expression vectors for either elucidate the genetic factors that KRT71: a new determinant of human wild-type or mutated KRT71 into control the shaping of hair fibers. hair texture human cell lines. They showed that Mutations in Krt71,knowntobe the mutation does not affect the CONFLICT OF INTEREST expressed throughout the IRS, have expression levels of KRT71, but instead The authors state no conflict of interest. been identified in mice, rats, and dogs, causes severe mislocalization of the protein, resulting in disruption of the and are linked to a wavy-coat pheno- REFERENCES type. Krt71 mutant mice (‘‘Caracul keratin intermediate filament network Cadieu E, Neff MW, Quignon P et al. (2009) mice’’) display wavy pelage and curvy owing to the inability of KRT71 to heter- Coat variation in the domestic dog is gov- vibrissae, which are inherited in an odimerize with KRT14 and KRT18. erned by variants in three genes. Science autosomal dominant manner (Kikkawa Although both KRT71 and KRT74 are 326:150–3 et al., 2003). Rex rats, which possess a implicated in WH phenotypes, the Chapalain V, Winter H, Langbein L et al. (2002) Is Krt71 mutation resulting in the deletion Japanese family with KRT71 mutations the loose anagen hair syndrome a keratin disorder? A clinical and molecular study. Arch of six amino acids, display curly hair in also displayed defects in facial hair, Dermatol 138:501–6 heterozygous mice and hair loss in whereas the previously reported Coulombe PA, Omary MB (2002) ‘‘Hard’’ and homozygous mice (Kuramoto et al., KRT74 mutation carriers showed a ‘‘soft’’ principles defining the structure,

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function and regulation of keratin inter- associated with monilethrix-like congenital van Steensel M, Steijlen PM, Bladergroen RS et al. mediate filaments. Curr Opin Cell Biol hypotrichosis. J Invest Dermatol 126:1281–5 (2005) A missense mutation in the type II hair 14:110–22 Shimomura Y, Wajid M, Ishii Y et al. (2008) keratin hHb3 is associated with monilethrix. Fuchs E (2007) Scratching the surface of skin Disruption of P2RY5, an orphan G protein- J Med Genet 42:e19 development. Nature 445:834–42 coupled receptor, underlies autosomal reces- Winter H, Rogers MA, Langbein L et al. (1997) sive woolly hair. Nat Genet 40:335–9 Mutations in the hair cortex keratin hHb6 Fujimoto A, Inoue A, Ohyama M et al. (2012) A cause the inherited hair disease monilethrix. missense mutation within the helix initiation Shimomura Y, Wajid M, Kurban M et al. (2010b) Nat Genet 16:372–4 motif of the keratin 71 (KRT71) gene under- Mutations in the keratin 85 (KRT85/hHb5) lies autosomal dominant woolly hair/ gene underlie pure hair and nail ectodermal Winter H, Schissel D, Parry DA et al. (2004) An hypotrichosis. J Invest Dermatol 132:2342–9 dysplasia. J Invest Dermatol 130:892–5 unusual Ala12Thr polymorphism in the 1A Shimomura Y, Wajid M, Petukhova L et al. (2010c) alpha-helical segment of the companion Inoue A, Arima N, Ishiguro J et al. (2011) LPA- Autosomal-dominant woolly hair resulting layer-specific keratin K6hf: evidence for a risk producing enzyme PA-PLA(1)alpha regulates from disruption of keratin 74 (KRT74), a factor in the etiology of the common hair hair follicle development by modulating potential determinant of human hair texture. disorder pseudofolliculitis barbae. J Invest EGFR signalling. EMBO J 30:4248–60 Am J Hum Genet 86:632–8 Dermatol 122:652–7 Kazantseva A, Goltsov A, Zinchenko R et al. (2006) Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH. Science 314:982–5 See related article on pg 2440 Kikkawa Y, Oyama A, Ishii R et al. (2003) A small deletion hotspot in the type II keratin gene mK6irs1/Krt2-6g on mouse 15, a candidate for causing the wavy hair of the Beyond ABC: Another Mechanism of caracul (Ca) mutation. Genetics 165:721–33 Kljuic A, Bazzi H, Sundberg JP et al. (2003) Drug Resistance in Melanoma Side Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphi- Population gus vulgaris. Cell 113:249–60 Mizuho Fukunaga-Kalabis1 and Meenhard Herlyn1 Kuramoto T, Hirano R, Kuwamura M et al. (2010) Identification of the rat Rex mutation as a It has been shown that a side population (SP), which is characterized by high 7-bp deletion at splicing acceptor site of the Krt71 gene. JVetMedSci72:909–12 chemical efflux capacity, is present in human melanoma cell lines. However, it was not clear whether patients’ samples contain the same subpopulation. In this Langbein L, Rogers MA, Winter H et al. (1999) The catalog of human hair keratins. Biochemistry issue, Luo et al. (2012) report that they have isolated SP cells directly from patients’ 274:19874–84 melanomas. SP cells are resistant to paclitaxel because of the upregulation of Langbein L, Schweizer J (2005) Keratins of the ABCB1 and ABCB5. Notably, these cells are also resistant to temozolomide, which human hair follicle. Int Rev Cytol 243:1–78 is not a substrate for ATP-Binding Cassette (ABC) transporters, in an interleukin Levy-Nissenbaum E, Betz RC, Frydman M et al. (IL)-8-dependent manner. This study provides novel clues for understanding how (2003) Hypotrichosis simplex of the scalp is a small, but critical, subpopulation within melanomas is resistant to therapies. associated with nonsense mutations in CDSN encoding corneodesmosin. Nat Genet The Journal of Investigative Dermatology (2012) 132, 2317–2319. doi:10.1038/jid.2012.220 34:151–3 Mils V, Vincent C, Croute F et al. (1992) The expression of desmosomal and corneodesmo- somal antigen shows specific variations dur- Melanomas are often resistant to that are evolutionary highly conserved ing the terminal differentiation of epidermal and hair follicle epithelia. J Histochem Cyto- pharmacological therapies. Conventional and have high sequence homology among chem 40:1329–37 chemotherapy drugs currently used in its members. These transporters regu- Naeem M, Jelani M, Lee K et al. (2006) Ectodermal clinics are of limited value in treating late tissue protection against endogenous dysplasia of hair and nail type: mapping of a advanced melanomas. Tumor shrinkage and exogenous cellular toxins. Some of novel locus to chromosome 17p12-q21.2. Br J induced by these drugs is often tempor- the ABC transporters are expressed ubiqui- Dermatol 155:1184–90 ary, and most tumors progress or relapse tously among diverse cancer cell lines Schaffer JV, Bazzi H, Vitebsky A et al. (2006) Mutations in the desmoglein 4 gene under- after short periods of time. Both intrin- (NCI-60), whereas others are expressed lie localized autosomal recessive hypo- sic and acquired mechanisms have roles selectively in cancer cells derived from trichosis with monilethrix hairs and con- in the chemoresistance of melanoma particular tissue types (Szakacs et al., genital scalp erosions. J Invest Dermatol 126:1286–91 cells. One of the key properties for intrin- 2004). Melanoma cells express a group sic resistance is the expression of certain of ABC transporters, including ABCA9, Schweizer J, Bowden PE, Pa Coulombe et al. (2006) New consensus nomenclature for ABC superfamily proteins, which function ABCB1, ABCB5, ABCB8, ABCC2, and mammalian keratins. JCellBiol174:169–74 as ATP-dependent efflux transporters. The ABCD1 (Chen et al., 2009). Although it Shimomura Y, Agalliu D, Vonica A et al. (2010a) ABC family comprises nearly 50 members hasbeenreportedthatABCB5andABCB8 APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature 464:1043–7 1Tumormicroenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA Shimomura Y, Sakamoto F, Kariya N et al. (2006) Correspondence: Meenhard Herlyn, Tumormicroenvironment and Metastasis Program, The Wistar Mutations in the desmoglein 4 gene are Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA. E-mail: [email protected]

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