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Genetics of Structural Hair Disorders

      Introduction

      The first successful application of positional cloning to a disorder of the skin involved the identification of steroid sulfatase as the gene mutated in X-linked ichthyosis (
      • Ballabio A.
      • Parenti G.
      • Carrozzo R.
      • et al.
      Isolation and characterization of a steroid sulfatase cDNA clone: genomic deletions in patients with X-chromosome-linked ichthyosis.
      ,
      • Yen P.H.
      • Allen E.
      • Marsh B.
      • et al.
      Cloning and expression of steroid sulfatase cDNA and the frequent occurrence of deletions in STS deficiency: implications for X-Y interchange.
      ). This groundbreaking discovery led to the cataloging of more than 500 unique protein-coding genes, underlying 560 different skin and hair abnormalities (
      • Feramisco J.D.
      • Sadreyev R.I.
      • Murray M.L.
      • et al.
      Phenotypic and genotypic analyses of genetic skin disease through the Online Mendelian Inheritance in Man (OMIM) database.
      ,
      • Betz R.C.
      • Cabral R.M.
      • Christiano A.M.
      • et al.
      Unveiling the roots of monogenic genodermatoses: genotrichoses as a paradigm.
      ). Among skin appendages, the hair follicle (HF) has a remarkably complex architecture, comprised of concentric layers of epithelial cells, which surround and support the highly keratinized, rigid hair shaft. The shaft itself consists of a multicellular cortex and the hair cuticle encased by the three layers of inner root sheath (IRS). The IRS is surrounded by the companion layer and the outer root sheath, which is continuous with the basal layer of the epidermis. With every successive hair cycle, the proliferating matrix cells in the anagen hair bulb differentiate and keratinize, giving rise to the layers of the IRS, as well as the cuticle, cortex, and medulla of the hair (
      • Langbein L.
      • Schweizer J.
      Keratins of the human hair follicle.
      ). Keratins, desmosomes, and lipids are abundantly expressed in the HF and are essential for maintenance of structural integrity and regulation of apoptosis, stress response, and protein synthesis (
      • Takahashi T.
      • Kamimura A.
      • Hamazono-Matsuoka T.
      • et al.
      Phosphatidic acid has a potential to promote hair growth in vitro and in vivo, and activates mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase in hair epithelial cells.
      ,
      • Gu L.-H.
      • Coulombe P.A.
      Keratin function in skin epithelia: a broadening palette with surprising shades.
      ,
      • Kim S.
      • Coulombe P.A.
      Intermediate filament scaffolds fulfill mechanical, organizational, and signaling functions in the cytoplasm.
      ). In this review, we will focus on hereditary hair disorders and discuss the studies that linked these disorders to genes encoding structural components of the HF.

      Keratins and Associated Hair Diseases

      Keratins are the major structural component of the HF and are generally divided into type I (acidic) and type II (neutral-basic) proteins. In addition to this classification, relating to chromosomal location, gene structure and ability to form heterodimers with the other type, keratins fall into two categories: keratins of the epidermis and the “hard” keratins of the hair. Hair keratins possess a highly cysteine-rich head and tail domains, allowing them to form tight cross links with keratin-associated proteins. This enables the formation of the tough structure of the hair and nails. Of the 54 functional keratin genes identified by the Human Genome Project, 11 type I keratins, designated as K31–K40, and 6 type II keratins, designated as K81–K86, are expressed specifically in HF and nails (
      • Langbein L.
      • Rogers M.A.
      • Winter H.
      • et al.
      The catalog of human hair keratins.
      ,
      • Schweizer J.
      • Bowden P.E.
      • Coulombe P.A.
      • et al.
      New consensus nomenclature for mammalian keratins.
      ). Keratin mutations cause fragility in epithelial cells and mutations in several hair keratins have been linked to human diseases (
      • McLean W.H.
      • Moore C.B.
      Keratin disorders: from gene to therapy.
      ).
      The first and most common among the hair keratin diseases is monilethrix, a nonsyndromic hair disorder characterized by fragile, brittle scalp hair, and nail deformities. Morphologically, affected individuals display periodic changes in hair shaft diameter, resulting in a characteristic abnormality called beaded hair. The autosomal dominant form of the disease is caused by missense mutations in the conserved helix termination motifs of the type II hair keratins KRT81, KRT83, and KRT86. These proteins are highly expressed in the hair cortex, and the identification of these mutations provided the first direct evidence for the involvement of hair keratins in hair disease (
      • Winter H.
      • Rogers M.A.
      • Langbein L.
      • et al.
      Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.
      ,
      • van Steensel M.
      • Steijlen P.M.
      • Bladergroen R.S.
      • et al.
      A missense mutation in the type II hair keratin hHb3 is associated with monilethrix.
      ). K85 is a type II hair keratin linked to autosomal recessive pure hair and nail ectodermal dyplasia, a disorder manifested as a complete alopecia and nail dystrophy. The K85 protein is abundantly expressed in the matrix, precortex, and cuticle of the hair shaft and appears critical for the proper formation of keratin and desmosomes complexes in the hair and nails. The severity of this phenotype suggests that K85 is more essential to HF structure than proteins involved in monilethrix (
      • Naeem M.
      • Jelani M.
      • Lee K.
      • et al.
      Ectodermal dysplasia of hair and nail type: mapping of a novel locus to chromosome 17p12-q21.2.
      ,
      • Shimomura Y.
      • Wajid M.
      • Kurban M.
      • et al.
      Mutations in the keratin 85 (KRT85/hHb5) gene underlie pure hair and nail ectodermal dysplasia.
      ). In addition to mutations in hair keratin genes, autosomal recessive mutations in a regulator of hair keratin gene expression, theFOXN1/WHN gene, result in alopecia and nail dystrophy (
      • Frank J.
      • Pignata C.
      • Panteleyev A.A.
      • et al.
      Exposing the human nude phenotype.
      ). This syndrome, which also includes T-cell immunodeficiency, represents the human counterpart to the nude mouse phenotype (
      • Nehls M.
      • Pfeifer D.
      • Schorpp M.
      • et al.
      New member of the winged-helix protein family disrupted in mouse and rat nude mutations.
      ).
      Of the epidermal keratins, type I keratins, K25–28, and type II keratins, K71–74, are abundantly and differentially expressed in the three layers of the IRS (
      • Langbein L.
      • Rogers M.A.
      • Praetzel-Wunder S.
      • et al.
      K25 (K25irs1), K26 (K25irs2), K27 (K25irs3), and K28 (K25irs4) represent the type I inner root sheath keratins of the human hair follicle.
      ,
      • Schweizer J.
      • Bowden P.E.
      • Coulombe P.A.
      • et al.
      New consensus nomenclature for mammalian keratins.
      ). Mutations in K71, identified in mice and dogs, are linked to the wavy coat phenotype called Caracul (
      • Kikkawa Y.
      • Oyama A.
      • Ishii R.
      • et al.
      A small deletion hotspot in the type ii keratin gene mK6irs1 / Krt2-6 g of the Caracul (Ca ) Mutation.
      ). Mutations in K74, which is highly expressed in Huxley’s layer of the IRS, are associated with autosomal dominant woolly hair (ADWH), a condition characterized by slow hair growth and tightly curled hair (
      • Shimomura 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.
      ). In addition, a recent study identified a missense mutation in K71 as the cause for ADWH in a Japanese family (
      • Fujimoto A.
      • Farooq M.
      • Fujikawa H.
      • et al.
      A missense mutation within the helix initiation motif of the keratin K71 gene underlies autosomal dominant woolly hair/hypotrichosis.
      ). Taken together, these findings suggest a role for keratins in hair disorders and determinants of normal hair texture variation across species (
      • Shimomura Y.
      • Christiano A.M.
      Biology and genetics of hair.
      ).

      Desmosomes and Associated Hair Disease

      Desmosomes are cell–cell adhesion complexes essential for morphogenesis, differentiation, and maintenance of tissues subjected to high mechanical stress, such as the skin and the heart. In both follicular and interfollicular epidermis, desmosomes anchor keratin intermediate filaments to the cell membranes and bind adjacent keratinocytes to each other, providing structural integrity and distribution of physical impact throughout tissue (
      • McGrath J.A.
      Inherited disorders of desmosomes.
      ,
      • Bazzi H.
      • Christiano A.M.
      Broken hearts, woolly hair, and tattered skin: when desmosomal adhesion goes awry.
      ). The major structural components of desmosomes are the desmosomal cadherin family composed of desmogleins (DSGs) and desmocollins (DSCs), and the cytoplasmic plaque proteins plakoglobin (PKG), plakophilins and desmoplakin (DSP) (
      • McGrath J.A.
      Inherited disorders of desmosomes.
      ).
      The importance of desmosome proteins to HF development and maintenance was first demonstrated by animal studies. Mutations in Dsg3 were shown to be responsible for the naturally occurringbalding mouse, and targeted ablation of this gene resulted in hair loss due to a defect in cell adhesion within the keratinocytes surrounding the club hair (
      • Koch P.J.
      • Mahoney M.G.
      • Cotsarelis G.
      • et al.
      Desmoglein 3 anchors telogen hair in the follicle.
      ). Dsg2-knockout mice die around the time of implantation, revealing the importance of this gene in general embryonic development (
      • Eshkind L.
      • Tian Q.
      • Schmid A.T.
      • et al.
      Loss of desmoglein 2 suggests essential functions for early embryonic development and proliferation of embryonal stem cells.
      ). More recently, a fourth member of the DSG family, DSG4, was shown to be the predominant DSG expressed in the HF (
      • Bazzi H.
      • Getz A.
      • Mahoney M.G.
      • et al.
      Desmoglein 4 is expressed in highly differentiated keratinocytes and trichocytes in human epidermis and hair follicle.
      ). DSG4 is a key mediator of keratinocyte cell adhesion in the HF, where it is expressed in the transition zone between proliferation and differentiation (
      • Kljuic 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.
      ). Mutations in DSG4 cause localized autosomal recessive hypotrichosis (LAH). LAH patients present with hypotrichosis limited to the scalp, chest, arms, and legs (
      • Kljuic 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.
      ). Some patients with DSG4 mutations display fragile hair shafts with beaded morphology, suggesting that DSG4 is the causative gene for the autosomal recessive form of monilethrix (
      • Schaffer 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.
      ,
      • Shimomura Y.
      • Sakamoto F.
      • Kariya N.
      • et al.
      Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis.
      ). Recently, a homozygous, nonsense mutation in DSC3 was reported to cause hypotrichosis and recurrent skin vesicles, a disorder that manifests as sparse scalp hair with fragile hair shafts and persistent fluid-filled skin vesicles (
      • Ayub M.
      • Basit S.
      • Jelani M.
      • et al.
      A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles.
      ). Corneodesmosin (CDSN), together with DSG1 and DSC1, form the modified desmosomes of the epidermis (corneodesmosomes). CDSN is expressed in the IRS, beginning at a later stage of keratinization and continuing until the IRS is degraded (
      • Mils 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.
      ), suggesting that CDSN has a role in terminal differentiation of the IRS. Indeed, heterozygous nonsense mutations in the CDSN gene cause hereditary hypotrichosis simplex restricted to the scalp. Histological examination of patients’ HF showed disruption of the IRS and aggregates of abnormal CDSN around the HF and the papillary dermis, implying that the mutant CDSN protein is acting in a dominantnegative manner (
      • Levy-Nissenbaum E.
      • Betz R.C.
      • Frydman M.
      • et al.
      Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin.
      ). Naxos and Carvajal syndromes are autosomal recessive disorders causing woolly hair (WH), palmoplantar keratoderma, and cardiomyopathy. These cardiocutaneous syndromes result from protein truncating mutations in the desmosomal components PKG and DSP, respectively (
      • McKoy G.
      • Protonotarios N.
      • Crosby A.
      • et al.
      Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease).
      ,
      • Norgett E.E.
      • Hatsell S.J.
      • Carvajal-Huerta L.
      • et al.
      Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma.
      ,
      • Bolling M.C.
      • Jonkman M.F.
      Skin and heart: une liaison dangereuse.
      ). Homozygous mutations in the PKG gene (both nonsense and splice site mutations) were also found to underlie skin fragility accompanied by WH, without heart abnormalities. Interestingly, one of these mutations resulted in very sparse WH, whereas patients harbouring the other mutation had abundant WH (
      • Cabral R.M.
      • Liu L.
      • Hogan C.
      • et al.
      Homozygous mutations in the 5’ region of the JUP gene result in cutaneous disease but normal heart development in children.
      ). Over 40 human mutations in the DSP gene have been shown to cause either skin or heart disease or a combination of skin, hair, and heart abnormalities, demonstrating the importance of this gene for the development and integrity of these tissues. DSP mutations can be associated with WH and hair loss (
      • Bolling M.C.
      • Jonkman M.F.
      Skin and heart: une liaison dangereuse.
      ).

      Lipids and Associated Hair Diseases

      Lipids are abundant both in the IRS of the HF and on the surface of the hair shaft cuticle, where they are covalently bound to hair proteins. Integral hair lipids form cell membranes that provide structural support and protect the hair shaft from environmental insults. Recent studies have demonstrated that lysophosphatidic acid (LPA), an active lipid with many biological functions, has a significant role in HF morphogenesis and cycling (
      • Takahashi T.
      • Kamimura A.
      • Hamazono-Matsuoka T.
      • et al.
      Phosphatidic acid has a potential to promote hair growth in vitro and in vivo, and activates mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase in hair epithelial cells.
      ). The first report linking lipid biology to hair disorders showed that mutations in lipase H (LIPH) cause autosomal recessive hypotrichosis (
      • Kazantseva A.
      • Goltsov A.
      • Zinchenko R.
      • et al.
      Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH.
      ). Subsequent reports have described other mutations in LIPH causing not only hypotrichosis, but also autosomal recessive WH (ARWH) (
      • Ali G.
      • Chishti M.S.
      • Raza S.I.
      • et al.
      A mutation in the lipase H (LIPH) gene underlie autosomal recessive hypotrichosis.
      ;
      • Nahum S.
      • Pasternack S.M.
      • Pforr J.
      • et al.
      A large duplication in LIPH underlies autosomal recessive hypotrichosis simplex in four Middle Eastern families.
      ;
      • Shimomura Y.
      • Wajid M.
      • Petukhova L.
      • et al.
      Mutations in the lipase H gene underlie autosomal recessive woolly hair/hypotrichosis.
      ). These patients feature slow or arrested hair growth, resulting in shorter length of the hair shaft. LIPH encodes a phospholipase responsible for the formation of LPA from phosphatidic acid. LPA signals by binding to the orphan G-protein-coupled receptor P2RY5, encoded by the LPAR6 gene (
      • Yanagida K.
      • Masago K.
      • Nakanishi H.
      • et al.
      Identification and characterization of a novel lysophosphatidic acid receptor, p2y5/LPA6.
      ). Both LIPH and LPAR6 are abundantly expressed in the IRS of the H and are likely involved in maintenance of hair shaft integrity. Accordingly, mutations in LPAR6 were also found to be associated with recessive hypotrichosis and WH. Affected individuals with LIPH or LPAR6 mutations displayed WH primarily during early childhood but then exhibit wide variability in hypotrichosis phenotype with aging (
      • Petukhova L.
      • Sousa Jr., E.C.
      • Martinez-Mir A.
      • et al.
      Genome-wide linkage analysis of an autosomal recessive hypotrichosis identifies a novel P2RY5 mutation.
      ,
      • Shimomura Y.
      • Wajid M.
      • Ishii Y.
      • et al.
      Disruption of P2RY5, an orphan G protein-coupled receptor, underlies autosomal recessive woolly hair.
      ). The range of phenotypes displayed by these patients suggests that they may be influence by other genetic or environmental factors, but taken together, these studies point at a role for LPA-mediated signaling in hair structure and growth.

      Hairless and APCDD1

      Although not strictly resulting in structural defects, mutations in two genes, hairless and APCDD1, underlie several important hair disorders. Atrichia with papular lesions (APL) is an autosomal recessive disorder characterized by early onset and complete hair loss, followed by the appearance of dermal cysts over the skin surface (
      • Ahmad W.
      • FuH M.
      • Brancolini V.
      • et al.
      Alopecia universalis associated with a mutation in the human hairless gene.
      ,
      • Panteleyev A.A.
      • Botchkareva N.V.
      • Sundberg J.P.
      • et al.
      The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation.
      ). Marie Unna hypotrichosis (MUH) is an autosomal dominant disease, presented as sparse scalp hair at birth, followed by complete alopecia or hypotrichosis in adulthood (
      • Lefevre P.
      • Rochat A.
      • Bodemer C.
      • et al.
      Linkage of Marie-Unna hypotrichosis locus to chromosome 8p21 and exclusion of 10 genes including the hairless gene by mutation analysis.
      ;
      • Sreekumar G.P.
      • Roberts J.L.
      • Wong C.Q.
      • et al.
      Marie Unna hereditary hypotrichosis gene maps to human chromosome 8p21 near hairless.
      ). Both syndromes are caused by mutations in the hairless (HR) gene. HR is a zinc finger transcription factor, postulated to function as a histone demethylase (
      • Shimomura Y.
      • Christiano A.M.
      Biology and genetics of hair.
      ). HR regulates the transition into catagen phase, including processes such as hair club formation, maintenance of dermal papilla–epithelial integrity, and IRS degradation. APL in humans, as well as in several animal models, is caused by homozygous loss-of-function mutations in HR. Strikingly, HR mutations result in abnormal degeneration of epithelial cells in the catagen HF, leaving behind the dermal papilla in the dermis (
      • Ahmad W.
      • FuH M.
      • Brancolini V.
      • et al.
      Alopecia universalis associated with a mutation in the human hairless gene.
      ,
      • Panteleyev A.A.
      • Botchkareva N.V.
      • Sundberg J.P.
      • et al.
      The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation.
      ). MUH-causing mutations were mapped to the 5’ UTR of the HR and the results are consistent with a gain of function and regulation at the translational level (
      • Wen Y.
      • Liu Y.
      • Xu Y.
      • et al.
      Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis.
      ).
      Hereditary hypotrichosis simplex, an autosomal dominant disorder, is characterized by degenerative HF miniaturization, leading to the conversion of thick terminal hair to fine vellus hair (
      • Toribio J.
      • Quinones P.A.
      Hereditary hypotrichosis simplex of the scalp. Evidence for autosomal dominant inheritance.
      ). APCDD1, a gene abundantly expressed in both epidermal and dermal compartments of the human HF, is mutated in this disease (
      • Shimomura Y.
      • Agalliu D.
      • Vonica A.
      • et al.
      APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
      ). APCDD1 has been implicated in linkage intervals in families with androgenic alopecia (
      • Hillmer A.M.
      • Flaquer A.
      • Hanneken S.
      • et al.
      Genome-wide scan and fine-mapping linkage study of androgenetic alopecia reveals a locus on chromosome 3q26.
      ) and alopecia areata (
      • Martinez-Mir A.
      • Zlotogorski A.
      • Gordon D.
      • et al.
      Genomewide scan for linkage reveals evidence of several susceptibility loci for alopecia areata.
      ). Our laboratory demonstrated that APCDD1 is an inhibitor of the Wnt signaling pathway, raising the possibility that APCDD1 may regulate Wnt-dependent processes in other cell types as well (
      • Shimomura Y.
      • Agalliu D.
      • Vonica A.
      • et al.
      APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
      ).

      Position Effects and Hypertrichosis

      A “position effect” is defined as an alteration in gene expression caused by a change in the position of a gene relative to its native chromosomal surroundings (
      • Kleinjan D.J.
      • van Heyningen V.
      Position effect in human genetic disease.
      ). Mechanisms may include chromosomal rearrangements, insertions, deletions, inversions, copy number variation (CNV) among others, thus these diseases tend to be very rare in the population. Paradoxically, a position effect may generate a distinct phenotype from the one(s) caused by loss-of-function mutations in the coding region of the same gene. For example, mutations in TRPS1, a zinc finger transcription factor with GATA and Ikaros-like domains, account for both hypo- and hypertrichosis disorders. Patients with Ambras syndrome display excessive ectopic hair growth and abnormal craniofacial features. Chromosomal rearrangements in these patients mapped to an interval on chromosome 8q, which includes TRPS1 (
      • Tadin M.
      • Braverman E.
      • Cianfarani S.
      • et al.
      Complex cytogenetic rearrangement of chromosome 8q in a case of Ambras syndrome.
      ,
      • Wuyts W.
      • Roland D.
      • Lüdecke H.-J.
      • et al.
      Multiple exostoses, mental retardation, hypertrichosis, and brain abnormalities in a boy with a de novo 8q24 submicroscopic interstitial deletion.
      ; Fantauzzo et al.,2008). Koala mice carry an inversion just upstream of the Trps1 gene and display excess hair on the muzzle and ears (
      • Fantauzzo K.A.
      • Tadin-Strapps M.
      • You Y.
      • et al.
      A position effect on TRPS1 is associated with Ambras syndrome in humans and the Koala phenotype in mice.
      ). In contrast, germline mutations in TRPS1 result in autosomal dominant inheritance of trichorhinophalangeal syndromes types I and III. These syndromes are characterized by sparse scalp hair, and craniofacial and skeletal abnormalities (
      • Momeni P.
      • Glöckner G.
      • Schmidt O.
      • et al.
      Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I.
      ,
      • Lüdecke H.J.
      • Schaper J.
      • Meinecke P.
      • et al.
      Genotypic and phenotypic spectrum in trichorhino-phalangeal syndrome types I and III.
      ). Deletion of the GATA-type zinc finger domain of Trps1 in mice mirrors the phenotype of human TRPS patients (
      • Malik T.H.
      • Von Stechow D.
      • Bronson R.T.
      • et al.
      Deletion of the GATA domain of TRPS1 causes an absence of facial hair and provides new insights into the bone disorder in inherited tricho-rhino-phalangeal syndromes.
      ). Analysis of these mutant mice revealed a role for Trps1 as a repressor of the expression of extracellular matrix proteins (
      • Fantauzzo K.A.
      • Christiano A.M.
      Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis.
      ). In addition to Ambras syndrome, two additional forms of hypertrichosis have been reported that result from position effects. Autosomal dominant hypertrichosis was linked to a microdeletion on 17q24, near the SOX9 gene (
      • Sun M.
      • Li N.
      • Dong W.
      • et al.
      Copy-number mutations on chromosome 17q24.2-q24.3 in congenital generalized hypertrichosis terminalis with or without gingival hyperplasia.
      ), suggesting that CNVs close to this gene, which encodes an essential regulator of HF stem cells (
      • Nowak J.A.
      • Polak L.
      • Pasolli H.A.
      • et al.
      Hair follicle stem cells are specified and function in early skin morphogenesis.
      ), may exert a position effect on the expression of SOX9 (
      • Sun M.
      • Li N.
      • Dong W.
      • et al.
      Copy-number mutations on chromosome 17q24.2-q24.3 in congenital generalized hypertrichosis terminalis with or without gingival hyperplasia.
      ). Generalized, X-linked hypertrichosis was mapped to chromosome Xq24-q27.1, however, no causative genes have been identified (
      • Figuera L.E.
      • Pandolfo M.
      • Dunne P.W.
      • et al.
      Mapping of congenital generalized hypertrichosis locus to chromosome X124-q27.1.
      ). A recent study revealed an interchromosomal insertion at Xq27.1 in a Chinese family with X-linked congenital hypertrichosis, and suggested that a position effect on SOX3, located upstream of the insertion site, may be responsible for the phenotype (
      • Zhu H.
      • Shang D.
      • Sun M.
      • et al.
      X-linked congenital hypertrichosis syndrome is associated with interchromosomal insertions mediated by a human-specific palindrome near SOX3.
      ), however, the specific genetic mechanism defect for X-linked hypertrichosis remains unknown.

      Summary

      The identification of causative genes carries the promise of new and innovative therapeutic strategies for both inherited and acquired hair disorders. Moreover, the delineation of the relationships between similar phenotypes, resulting from mutations affecting seemingly distinct regulatory pathways, paves the way to improved diagnosis and treatment. Finally, understanding the biological processes governing HF development and maintenance may have implications for more general disease processes in the skin, such as inflammation and cancer.

      Conflict of Interest

      The authors state no conflict of interest.

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