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Unveiling the Roots of Monogenic Genodermatoses: Genotrichoses as a Paradigm Regina C. Betz1, Rita M. Cabral2, Angela M. Christiano2 and Eli Sprecher3,4

The past two decades have seen significant and homeostasis. Second, it provides advances in disease unprecedented progress in human genetics owing classification, by merging diseases that manifest with slightly to the advent of novel molecular biological technol- different phenotypes into a physiological grouping that ogies and major developments in computational harbors unique entities at the molecular level. The simplifica- methods. has benefited from and, in tion of disease categorization and elimination of redundant some cases, led these advances. In this article, we terminology has implications for the improvement of review major discoveries in the field of inherited diagnostic accuracy, optimization of genetic counseling, diseases, which illustrate the changes that genoder- and sets the stage for the development of therapeutic and matology has undergone in recent years from a mostly preventive approaches for these genodermatoses (McGrath, descriptive discipline through the elucidation of the 2004). A major translational benefit of molecular research in dermatology is the feasibility and development of prenatal molecular basis of numerous disorders, up to the first diagnosis for couples at risk of recurrence of severe inherited attempts at translating these new findings into novel skin diseases, such as the lethal skin blistering disease preventive and therapeutic tools to the benefit of our or disorders manifesting with mild patients. dermatological phenotypes, but heralding severe extracuta- Journal of Investigative Dermatology (2012) 132, 906–914; doi:10.1038/ neous features such as blindness in hypotrichosis with jid.2011.408; published online 15 December 2011 juvenile macular dystrophy (HJMD; Online Mendelian Inheritance in Man (OMIM) 601553) and life-threatening arrhythmias in Naxos disease (OMIM 601214). Prenatal INHERITED SKIN DISORDERS THROUGH TIME testing for genodermatoses has been performed since the During the past 20 years, major breakthroughs in genomic 1980s, based initially on mid-trimester fetal skin biopsies, techniques have facilitated considerable progress toward later on DNA-based methods at B10–12 weeks of gestation, unraveling the molecular basis of inherited skin diseases and more recently on preimplantation genetic screening (Figure 1). At present, over 6,000 Mendelian disorders are (Fassihi and McGrath, 2010). known, of which B560 involve skin abnormalities and are identification in the early days was laborious, and associated with more than 500 unique -coding relied mainly on two main approaches: positional cloning (Feramisco et al., 2009). The successful identification of a and candidate gene analysis, as well as extensive clinical growing number of genes and pathogenic respon- observation and familial segregation of the disease. The first sible for monogenic skin disorders has had a profound impact successful application of this approach led to the delineation on the field of clinical genetics. First, coupled with functional of the molecular basis of X-linked (OMIM 308100) studies, gene discovery constitutes an indispensable tool to in 1987. This discovery stemmed from a number of initial understand disease pathogenesis and to indirectly gain insight studies including X-linked ichthyosis mapping to chromo- into the functions of encoded in normal skin some X 20 years before the characterization of the underlying molecular defect (Kerr and Wells, 1964). The fact that offspring of individuals with the placental sulfatase deficiency 1Institute of Human Genetics, University of Bonn, Bonn, Germany; 2Departments of Dermatology and Genetics and Development, Columbia syndrome also presented with ichthyosis pointed to the STS University, New York, New York, USA; 3Department of Dermatology, (steroid sulfatase) gene as a likely candidate (Shapiro et al., Tel Aviv Sourasky Medical Center, Tel Aviv, Israel and 4Department of 1978). Finally, large deletions at the STS locus were identified Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, by using an STS clone isolated from a complementary DNA Tel Aviv University, Ramat Aviv, Israel library as the probe for Southern blot hybridizations (Ballabio Correspondence: Eli Sprecher, Department of Dermatology, Tel Aviv Sourasky Medical Center, 6, Weizmann Street, Tel Aviv 64239, Israel. et al., 1987; Yen et al., 1987). In the early 1990s, similarly E-mail: [email protected] designed studies using a combination of genetic linkage Abbreviations: APL, atrichia with papular lesions; HJMD, hypotrichosis with studies, ultrastructural analysis of skin biopsies, and reverse juvenile macular dystrophy; LPA, lysophosphatidic acid; MUHH, Marie Unna genetics led to the elucidation of the molecular basis of a hereditary hypotrichosis; NGS, next-generation sequencing; OMIM, Online large number of important genodermatoses, including epi- Mendelian Inheritance in Man; ORF, open reading frame; VDR, vitamin D receptor dermolysis bullosa simplex (OMIM 131760) caused by Received 19 July 2011; revised 24 August 2011; accepted 26 August 2011; mutations in the KRT5 and KRT14 genes (Bonifas et al., published online 15 December 2011 1991; Coulombe et al., 1991; Lane et al., 1992) and

906 Journal of Investigative Dermatology (2012), Volume 132 & 2012 The Society for Investigative Dermatology RC Betz et al. Unveiling the Roots of Monogenic Genodermatoses

Full-length cDNA Southern blot, DNA fingerprinting, technologies, Sanger Electrophoresis PCR invented RNAi sequencing Whole- 1952 1998 Semiconservative published genome 1985 Successful Next-generation DNA replication shown 1975 shotgun gene therapy DNA sequencing 1958 1982 1990 2005

1953 1972 1977 1980 1987 1995 2001 DNA double helix Development of First RFLP Site-directed Microarray Draft of human structure described recombinant genome concept mutagenesis technology genome released technology sequenced of the mouse 1966 (FX174) genome Genetic code 1983 cracked First human disease gene mapped with DNA markers (HD)

Figure 1. DNA milestones timeline. Major discoveries and breakthroughs in genomic technologies over the past 50 years are shown, which have allowed the enormous advances in the field of inherited skin diseases as well as many other hereditary disorders. cDNA, complementary DNA; HD, Huntington disease; RFLP, restriction fragment length polymorphism; RNAi, RNA interference. autosomal recessive congenital ichthyosis (OMIM 242300) available to study disorders that are not amenable to linkage caused by mutations in TGM1 (Huber et al., 1995). Later in analysis, because of small family size, for example. Whereas the 1990s, structural analysis of anchoring fibrils in patients whole-exome sequencing is powerful to identify mutations in with different forms of dystrophic epidermolysis bullosa, the coding region and splice-site mutations (which account coupled with linkage studies using restriction fragment length for most monogenic diseases), whole-genome sequencing polymorphisms, also resulted in the discovery of mutations allows the additional identification of mutations in nontrans- underlying the dystrophic forms of epidermolysis bullosa lated regions and other regulatory elements (Ku et al., 2011). (Ryynanen et al., 1992; Christiano et al., 1993; Hilal et al., These novel techniques have already been proven successful 1993). Restriction fragment length polymorphism analysis, in identifying new pathogenic mutations in skin diseases. For which involves restriction digestions followed by Southern example, a in ADAM17 underlying an autosomal blotting, was the first DNA-based technique used in genomic recessive inflammatory skin and bowel disease was very mapping, disease-associated gene mapping, as well as recently identified using a combination of homozygosity determination of disease risk and paternity testing. Owing genome-wide single-nucleotide polymorphism mapping and to the transformative discovery of PCR and the emergence of targeted sequence capture, followed by NGS (Blaydon et al., inexpensive DNA sequencing technologies, this cumbersome 2011). This exciting new era looks promising to elucidate the technique has been largely replaced by PCR-based linkage genetic cause of over 3,000 monogenic disorders, the cause methods such as short tandem repeat analysis. This method of which remains currently unknown. consists of the PCR amplification of short tandem repeats (or microsatellites), which are units of 2–13 nucleotides that are FROM PHENOMICS TO GENETICS: HAIR DISORDERS AS repeated hundreds of times in a row on a DNA strand, to AN EXAMPLE resolve their segregation patterns within families. Careful phenotypic characterization is immensely important The completion of the human genome project in 2003 for the successful identification of causative genes in marked a crucial turning point in modern genetics research. inherited disorders in general, and in genodermatoses more At present, genome-wide techniques, such as genotyping specifically. In turn, the elucidation of the genetic under- arrays and next-generation sequencing (NGS), are available pinning of a given phenotype often reveals genotype–pheno- and are complementing or replacing traditional methods. type correlations of potential use for the reclassification of Genotyping array technology, which allows the genotype clinical entities and their treatment. determination of 104 to 2 106 single-nucleotide polymor- Inherited hair disorders are no exception to this rule. More phisms simultaneously, is currently widely used for linkage than 300 inherited disorders featuring hair abnormalities have analysis because it is faster and allows generation of much been cataloged to date, and yet, in a substantial portion of denser linkage maps than the traditional microsatellite-based these, no genetic defect has been identified. These disorders linkage analysis. The main weakness of this method is the are, as a group, often extraordinarily challenging from a need for large pedigrees with several affected individuals to diagnostic point of view because of a high degree of achieve statistical significance. This problem is mainly of phenotypic overlap. Many classifications have been put relevance in the study of autosomal dominant disorders. forward in an attempt to facilitate their diagnosis (Sprecher, Autosomal recessive conditions can usually be solved more 2005; Schweizer et al., 2007; Cheng and Bayliss, 2008). easily in small consanguineous families exhibiting identity by Genetically determined abnormal hair growth can either descent using homozygosity mapping (Alkuraya, 2010). manifest as excess of hair () or lack of hair Whole-exome and whole-genome sequencing are now (hypotrichosis/alopecia/atrichia). Disorders characterized by

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excess of hair are known as hypertrichoses, which can Human and mouse hairless proteins have highly homo- manifest either in a generalized or localized manner. It is logous amino-acid sequences, which suggest high conserva- interesting to note that most inherited forms of generalized tion and functional importance of hairless. This protein is a hypertrichosis have been shown to result from complex potential zinc-finger that harbors a chromosomal rearrangements, which has led some authors to jumonji C domain, which is a structural domain contained suggest that they may be better viewed as genomic rather by histone demethylases. Accordingly, hairless was recently than genetic disorders (Fantauzzo et al., 2008; Sun et al., shown experimentally to display histone demethylase func- 2009; Zhu et al., 2011). Most types of localized hyper- tion, and therefore may have a role in the epigenetic trichoses are, in contrast, part of complex syndromes and are regulation of the hair cycle (Shimomura and Christiano, due to discrete sequence alterations, as exemplified by the 2010; Liu et al., 2011). recently described ‘‘H’’ syndrome, due to mutations in the Several lines of evidence indicate that hairless function is SLC29A3 gene (Molho-Pessach et al., 2008). necessary for hair cycling, but not for hair follicle morpho- Hair disorders associated with sparse hair can grossly be genesis. Hairless is an important regulator of the catagen characterized into two major groups according to the absence phase, including processes such as club hair formation, (nonsyndromic) or presence (syndromic) of extracutaneous maintenance of dermal papilla–epithelial integrity, inner root features. For example, children with hypotrichosis inherited sheath disintegration, and keratinocyte apoptosis in the hair in an autosomal recessive manner can either display short follicle matrix (Panteleyev et al., 2000). Interestingly, muta- and sparse hair in isolation (Kazantseva et al., 2006) or in tions in the VDR (vitamin D receptor) gene result in a hair association with nondermatological features such as retinal scalp phenocopy of APL (Hughes et al., 1988), reflecting the degeneration in HJMD (Souied et al., 1995), in fact that hairless function is, in part, dependent on its hypotrichosis–lymphedema–telangiectasia syndrome (OMIM interaction with VDR (Skorija et al., 2005). 607883; Irrthum et al., 2003), and severe immunodeficiency In addition to APL and related recessive phenotypes, Marie in T-cell immunodeficiency, congenital alopecia, and Unna hereditary hypotrichosis (MUHH; OMIM 146550), dystrophy syndrome (OMIM 601705; Frank et al., 1999). a dominant form of hypotrichosis, was also mapped to These two groups of disorders can be further subdivided into the hairless locus 10 years ago. Individuals with MUHH are diseases associated with scarring alopecias, as in ichthyosis born with sparse scalp, body, and facial hair (including follicularis, alopecia, and photophobia syndrome (OMIM eyebrows and eyelashes). In early childhood, they develop 308205), caused by mutations in the MBTPS2 gene (Oeffner coarse, wiry, twisted hair, followed by the progressive et al., 2009), or nonscarring alopecias. Non-scarring alopecias development of alopecia at . Total alopecia or bald can in turn be subclassified into three classes of disorders lesions resembling androgenetic alopecia can be observed characterized by a total absence of hair (atrichia), as exempli- later in life. fied by atrichia with papular lesions (APL; OMIM 209500), or MUHH was initially mapped to 8p, in a a paucity of hair (hypotrichosis), as seen in hypotrichosis region containing the hairless gene, using a genome-wide simplex of the scalp (OMIM 146520) or abnormal hair shaft linkage approach in a large Dutch family (van Steensel et al., structure, as in (OMIM 158000) or Netherton 1999). Several studies further confirmed linkage of the syndrome (OMIM 256500; Figure 2). disease to chromosome 8p21 (Lefevre et al., 2000; Sreekumar This phenotypic classification has served as a conceptual et al., 2000; He et al., 2004). However, numerous subsequent framework for an international effort that has led over the past attempts at finding hairless mutations in MUHH repeatedly years to the elucidation of the molecular basis of most major failed and it was not until a decade after the initial mapping forms of inherited hair disorders. These achievements have of the disease that its underlying cause was finally identified. in turn radically changed our understanding of fundamental Using bioinformatics and sequencing analysis of reverse- aspects of hair biology while also allowing for prenatal transcriptase–PCR products from A375 and HeLa cell lines, diagnosis (where appropriate) and paving the way for novel Wen et al. (2009) discovered the existence of four previously therapeutic interventions. The following section encapsulates unknown open reading frames (ORFs) located upstream of three lines of research that illustrate these principles. the main hairless ORF, which they named U1HR–U4HR. ORFs within the 50-untranslated regions of mRNA transcripts FROM MONOGENIC DISEASES TO HAIR BIOLOGY: can alter the translational efficiency of the main ORF. THREE SHORT STORIES Disruption of upstream ORFs has been reported as the cause Hairless-associated disorders of noncutaneous inherited diseases in humans (Cazzola and APL (OMIM 209500) is characterized by early-onset and Skoda, 2000). Interestingly, it has been shown in mice that complete , upon which small erythematous papules anagen hair follicles express hairless mRNA but not protein, appear over most parts of the skin surface, because of the suggesting regulation at the translational level (Beaudoin development of dermal after a defective first catagen et al., 2005). Through direct sequencing of all four 50- phase of the hair cycle (Figure 3). Homozygous loss-of- untranslated region ORFs in 19 families with MUHH from function mutations in the hairless (HR)genewerefoundto different ancestral groups, a total of 13 distinct U2HR single- cause APL in humans (Ahmad et al., 1998; Cichon et al., 1998; nucleotide substitutions were found (Wen et al., 2009). Sprecher et al., 1999), as well as related phenotypes in various Functional studies showed that U2HR mutations result in animals (Cachon-Gonzalez et al., 1999; Ahmad et al., 2002). increased hairless protein expression, leading the authors to

908 Journal of Investigative Dermatology (2012), Volume 132 RC Betz et al. Unveiling the Roots of Monogenic Genodermatoses

Figure 2. Clinical classification of inherited alopecias. Hair disorders featuring defective hair growth or differentiation can be classified into three major types: (a) total absence of hair termed atrichia as shown here in a patient with atrichia with papular lesions (APL); (b) paucity of hair known as hypotrichosis as shown in a young girl affected with hypotrichosis with juvenile macular dystrophy (HJMD); and (c) diseases caused by abnormal hair shaft structure such as monilethrix featuring short and easily breakable hair, displaying typical beading under the microscope (lower insert).

Telogen Nonsyndromic and syndromic hypotrichoses Nonsyndromic hypotrichoses form a complex, heteroge- neous, and clinically challenging group of disorders. The genetic etiopathogenesis of autosomal recessive hypotricho- Anagen VI Catagen VIII sis started to unfold through the study of two populations from the Volga–Ural region in Russia, in which a single deletion in the lipase H (LIPH) gene caused by short Club hair interspersed nuclear element-mediated recombination (Kazantseva et al., 2006) was found to cause localized autosomal recessive hypotrichosis type 2 (LAH2; OMIM Remnants 604379) (Kazantseva et al., 2006). Subsequent reports Outer root of the inner root sheath described this and other mutations in LIPH in different sheath Hair cycle Melanocytes Dermal papilla regions of the world in individuals featuring not only Hair matrix hypotrichosis but also woolly hair (Ali et al., 2007; Nahum et al., 2009; Shimomura et al., 2009b). The hair growth of Catagen II Catagen VI these patients is generally slowed or arrested, which results in a shortened length of the hair shaft. LIPH encodes a phospholipase known as lipase H. This enzyme is responsible Zone of for the formation of lysophosphatidic acid (LPA) from trichilemmal keratinization phosphatidic acid. LPA can elicit signal transduction by binding to the orphan G-protein–coupled receptor, P2Y5 Perifollicular (Pasternack et al., 2009b). Accordingly, localized autosomal connective tissue sheath recessive hypotrichosis type 3 (LAH3; OMIM 611452) and Inner root Club hair woolly hair were also found to result from mutations in sheath Epithelial LPAR6, encoding P2Y5 (Azeem et al., 2008; Pasternack et al., strand Dermal 2008; 2009a; Shimomura et al., 2008a, 2009a; Tariq et al., papilla 2009; Horev et al., 2010; Nahum et al., 2011). Taken together, these data demarcate a critical new pathway of Figure 3. Schematic representation of the hair cycle and hairless mRNA importance for proper hair growth and structure involving expression patterns. Two different intensities, low and high, are shown in dark pink and red, respectively, indicating lower and higher expression of lipase H, LPA, and its receptor, P2Y5. hairless mRNA during late anagen–catagen–telogen progression in depilation- Hypotrichosis is not only seen in humans as an isolated induced hair follicle cycling (adapted from Panteleyev et al., 2000 and feature but can also be part of complex syndromes. Salient Shimomura and Christiano, 2010). examples include hypohidrotic asso- ciated with mutations in EDA, EDAR,orEDARADD suggest that a small peptide encoded by wild-type U2HR (Mikkola, 2009), autosomal recessive ichthyosis with hypo- decreases the expression of hairless at the translational level trichosis (OMIM 610765) associated with mutations in ST14 (Wen et al., 2009). Thus, both increased and decreased encoding matriptase (Basel-Vanagaite et al., 2007), alopecia, hairless activity result in an abnormal hair phenotype, neurological defects, and endocrinopathy syndrome (OMIM MUHH and APL, respectively. 612079) associated with mutations in RBM28 (Nousbeck

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et al., 2008), Naxos disease associated with mutations in JUP is caused by mutations in DSG4, encoding desmoglein 4 encoding (Protonotarios and Tsatsopoulou, (Schweizer, 2006), unless it is associated with nail dystrophy, 2004), and HJMD associated with mutations in CDH3 in which case mutations in KRT85 are generally found (Sprecher et al., 2001). (Naeem et al., 2006). DSG4 is localized within the HJMD is transmitted as an autosomal recessive trait and desmosomal gene cluster on chromosome 18 and manifest with sparse and short hair at birth, most probably represents a key mediator of keratinocyte cell adhesion in the due to prolonged telogen (Bergman et al., 2004). These hair follicle. Patients with mutations in DSG4 present with cutaneous features herald progressive hair that is typically fragile and prone to break easily, leading during the first to second decade of life, culminating with to short sparse scalp hair, as well as to occasional swellings of blindness by 20 years of age. Although some patients with the hair shaft (Kljuic et al., 2003). HJMD display fair hair complexion (Indelman et al., 2003) Syndromic hair shaft disorders encompass a wide range of and limb abnormalities (Kjaer et al., 2005) (then referred to inherited syndromes including (OMIM as EEM (ectodermal dysplasia, , and macular 256500) featuring trichorrhexis invaginata, atopy, and dystrophy syndrome); OMIM 225280), HJMD is often not , and caused by mutations in SPINK5 (Chavanas distinguishable from other forms of hypotrichosis, and thus et al., 2000); hypotrichosis with recurrent vesicles (OMIM fundus examination and electrophysiological testing are 613102) associated with mutations in DSC3 (Ayub et al., mandatory in any new case of congenital hypotrichosis. 2009); the tricho-hepato-enteric syndrome (OMIM 222470), HJMD-causing mutations in CDH3 result in decreased characterized by , liver disease, and expression of P-cadherin, a major constituent of adherens chronic diarrhea, and caused by mutations in TTC37 junctions. Although the role of P-cadherin in maintaining (Chavanas et al., 2000; Hartley et al., 2010); and Bjo¨rnstad normal hair growth remains to be fully elucidated, it is syndrome (OMIM 262000). Bjo¨rnstad syndrome remarkably likely to be related to the fact that a large pool of b-catenin, illustrates the complexity of the molecular genetics of this which serves as a key regulator of hair development, growth, group of disorders. The disease is transmitted in an autosomal and differentiation, is normally bound to the cytoplasmic recessive manner and features (1801 twisting of hair plaques of adherens junctions (Fuchs, 2007). More recently, shafts) associated with sensorineural hearing loss (Selvaag, P-cadherin expression was found to be dependent upon 2000). Bjo¨rnstad syndrome was found to result from p63 signaling (Shimomura et al., 2008b). These findings mutations in BCS1L, which encodes a member of the AAA may explain the occasional occurrence of limb abnormalities family of ATPases that are necessary for the assembly of in HJMD/EEM syndrome, which are a hallmark of p63 complex III in the mitochondria. Surprisingly, mutations in syndromes (Brunner et al., 2002). the very same gene also cause complex III deficiency and the As a final note, overlapping clinical manifestations of GRACILE (growth retardation, aminoaciduria, cholestasis, mutations affecting distinct genes should always raise the iron overload, lactic acidosis and early death) syndrome possibility that the products of these genes may function (OMIM 603358), which are lethal conditions characterized along a common biochemical pathway. In this regard, it is by severe multisystem manifestations (Visapaa et al., 2002; of interest that the P2Y5 receptor, which is defective in De Meirleir et al., 2003). How do we explain the fact that autosomal recessive nonsyndromic hypotrichosis, was shown mutations in one same gene lead to such divergent pheno- to be physiologically expressed in close association with types? Whereas Bjo¨rnstad syndrome-associated mutations classical (Pasternack et al., 2008). only affect residues involved in protein–protein interactions, mutations causing complex III deficiency alter ATP-binding Hair shaft abnormalities residues, resulting in a particularly strong increase in the As mentioned above, it is often difficult to draw a clear line production of reactive oxygen species, thus providing the between hypotrichoses and hair shaft disorders, as patients molecular rationale for the heterogeneous phenotypic mani- with diseases primarily resulting from abnormal hair structure festations of mutations in BCS1L. often also manifest clinically with hypotrichosis. As with atrichias and hypotrichoses, hair shaft disorders can manifest FROM GENETICS BACK TO PHENOMICS: TOWARD A as solitary diseases or be part of complex constellations RECLASSIFICATION OF INHERITED HAIR DISORDERS of signs. As briefly outlined above, the past years have witnessed Monilethrix can be viewed as a prototypic hair shaft significant advances in our understanding of the pathogenesis disorder (Schweizer et al., 2007). Clinically, classical of genotrichoses. This new knowledge is now resulting in a monilethrix manifests with short and brittle hair, leading to reorganization of our classification systems in this group of the clinical appearance of hypotrichosis. In addition, patients diseases, which, instead of being solely founded on clinical can present additional cutaneous features including nail findings, now integrates both clinical and molecular features. dystrophy and follicular papules. Severity is highly variable, Congenital hypotrichoses epitomize the conceptual changes and improvement over time has often been reported. When derived from these recent findings, and are used here as a inherited as a dominant trait, monilethrix is usually due to representative example. As demonstrated in Figure 4, it is mutations in genes encoding hair , including KRT81, now possible to assign most forms of hypotrichosis to one KRT83, and KRT86 (Winter et al., 1997a, 1997b; van Steensel gene (or group of genes) on the basis of a very limited amount et al., 2005). When inherited as a recessive trait, monilethrix of information concerning three clinical features: mode of

910 Journal of Investigative Dermatology (2012), Volume 132 RC Betz et al. Unveiling the Roots of Monogenic Genodermatoses

Hypotrichosis Recessive Dominant

± Woolly hair ± Monilethrix

Nonsyndromic Syndromic Nonsyndromic Syndromic Nonsyndromic Syndromic

Hypotrichosis Naxos Monilethrix Pure hair Normal Hair shaft simplex Carvajal nail ED hair shaft anomaly HJMD ARIH LIPH ANE DSG4 KRT85 Hypotrichosis Woolly hair Ectodermal LPAR6 HRSV simplex Monilethrix dysplasias DSG4 NTS Björnstad APCDD1 KRT74 KRT83 EDAR JUP RBM28 CDSN KRT81 KRT86 EDARRAD DSP DSC3 RPL21 SOX18 CDH3 SPINK5 ST14 BCS1L

Figure 4. Clinicogenetic classification of hypotrichoses. Using three clinical criteria, most patients with hypotrichosis can be assigned to a group of molecularly defined hair disorders. ANE, alopecia, neurological defects, and endocrinopathy; ARIH, autosomal recessive ichthyosis with hypotrichosis; DSG4, desmoglein 4; ED, ectodermal dysplasia; EDAR, ectodysplasin A receptor; EDARADD, EDAR-associated death domain; HJMD, hypotrichosis with juvenile macular dystrophy; HRSV, hypotrichosis with recurrent vesicles; KRT85, 85; LIPH, lipase H; LPAR6, lysophosphatidic acid receptor 6; NTS, Netherton syndrome. inheritance, the presence or absence of associated features, et al., 2009). However, both in dermatology and in other and microscopic appearance of the hair shaft. Once these fields, the molecular basis of a substantial number of data are available, it is easy to decide about the optimal inherited or congenital disorders remain elusive, highlight- molecular diagnostic strategy and genetic testing that is likely ing the need for the development of novel technologies to lead to the correct diagnosis. For example, using the capable of circumventing the weaknesses of currently algorithm outlined in Figure 4, a patient with a dominant available strategies. form of hypotrichosis, not associated with any extracutaneous Within the past few years, the advent of NGS techniques features and without any evidence for monilethrix under the has paved the way for genetic investigations that can be microscope, is likely to carry a mutation in either the CDSN conducted regardless of family structure or trait penetrance. A gene, encoding corneodesmosin (Levy-Nissenbaum et al., full review of the range of equipment systems that are used 2003), or in the APCDD1 gene, encoding a WNT inhibitor today is beyond the scope of the present article and has been (Shimomura et al., 2010). In contrast, if a patient is affected reviewed thoroughly elsewhere (Schadt et al., 2010; Pareek by a recessive form of alopecia and also suffers from nail et al., 2011). It suffices here to state that NGS can be used to dystrophy, then he/she is more likely to carry mutations in the generate large volumes of sequence data, ranging from KRT85 gene (Naeem et al., 2006). discrete genomic regions through exome sequences and up to the whole genome. The first successful application of exome WITHIN A HAIR’S BREADTH FROM THE END: WHAT’S sequencing led to the identification of the genetic under- ‘‘NEXT’’ IN GENOTRICHOSES? pinnings of two rare Mendelian disorders: Miller syndrome The past three decades have demonstrated the formidable (Ng et al., 2010) and Schinzel–Giedion syndrome (Hoischen potential of classical linkage and candidate gene approaches. et al., 2010). These successes were achieved by massive However, as successful as this strategy has been in leading to parallel sequencing of 180,000 exons across the human the deciphering of the molecular basis of skin monogenic genome. The use of the very same technique recently led to disorders, it is not without limitations. Indeed, this methodol- the identification of a new gene in hypotrichosis simplex. In ogy performs suboptimally under three situations: small-size this study, Zhou et al. (2011) mapped the disease to a known families/single individuals, low-penetrance traits, and vary- gene locus on chromosome 13q12 (Xu et al., 2010) and ing/subtle phenotypes, complicating the definition of affected studied a single individual by exome target enrichment status. These constraints are of little importance in the and NGS in the linked region. By combining the mapping presence of an obvious candidate gene, as exemplified by and sequencing data, a sequence variant in RPL21, encoding the identification of a dominant variation in KRT75 conferring the ribosomal protein L21, was shown to underlie the disease propensity to pseudofolliculitis barbae (Winter et al., 2004). (Zhou et al., 2011). Additional examples of the use of NGS in In other cases, the spectrum of candidate genes can be investigative dermatology include two recent confirmatory narrowed by combining linkage and expression data even studies implicating genes encoding components of g-secre- when only few affected individuals are available as recently tase in inversa (Liu et al., 2011; Pink et al., 2011); the demonstrated in a rare form of (Basel-Vanagaite discovery of the gene associated with terminal osseous

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PA EDAR for the treatment of inherited, and possibly acquired, LIPH EDARADD Polyamines hair disorders. Indeed, the translation of the new findings LPA reviewed over these pages into innovative therapeutic VDR strategies should be regarded as one of our most important Hr ODC goals. Initial steps in that direction have already been taken. LPAR6 VDR WISE For example, we mentioned the new pathway recently Lef-1 uncovered through the study of rare forms of hypotrichosis, Cadherins HK β-Catenin which involves lipase H, LPA, and its receptor, P2RY5 (Kazantseva et al., 2006; Pasternack et al., 2008; Shimomura et al., 2008a). The delineation of such a new pathway clearly FZD offers new possibilities for therapeutic interventions aimed at inhibiting or promoting hair growth. In this regard, it is of WNT interest to note that LPA has already been shown to stimulate Figure 5. Overlapping phenotypes and pathogenesis in inherited hair hair growth in mice (Takahashi et al., 2003). Similarly, disorders. The data that have accumulated over the past years suggest that selective inhibition of the hairless protein has been shown to most inherited hair disorders result from defective functions of biologically lead to decreased hair growth (Cserhalmi-Friedman et al., related pathways. This scheme summarizes the interactions known between 2004), a finding that may form the basis for a new approach the molecules defective in the various disorders mentioned in the text. Arrows to the treatment of diseases as common as female . symbolize a promoting effect, whereas perpendicular streaks denote an inhibitory effect. EDAR, ectodysplasin A receptor; EDARADD, EDAR- In summary, 15 years after the identification of the first associated death domain; FZD, frizzled receptor; HK, hair keratins; skin disease–causing mutations in humans (Ballabio et al., Hr, hairless; LIPH, lipase H; LPA, lysophosphatidic acid; ODC, ornithine 1987; Yen et al., 1987), it is evident that the study of decarboxylase; PA, phosphatidic acid; P2RY5, P2Y purinoceptor 5 cutaneous monogenic disorders has had an enormous impact (also known as LPAR6, lysophosphatidic acid receptor 6); VDR, vitamin D within and outside our field, not only broadening our receptor; WISE, context-dependent activator and inhibitor of Wnt signaling understanding of hair biology, but, more importantly, paving protein (also known as SOSTDC1, sclerostin domain containing 1); the way for improved diagnosis, and prevention and WNT, Wingless-type MMTV integration site family. treatment of skin diseases, inherited and acquired alike.

dysplasia (OMIM 300244; Sun et al., 2010), an X-linked CONFLICT OF INTEREST dominant disease characterized by pigmentary defects of the The authors state no conflict of interest. skin, skeletal dysplasia of the limbs, and recurrent digital fibroma; and the deciphering of the molecular etiology of ACKNOWLEDGMENTS Regina C. Betz is recipient of a Heisenberg Professorship from the German Clericuzio-type poikiloderma with neutropenia (OMIM Research Foundation (DFG). 604173; Volpi et al., 2010), a rare autosomal recessive characterized by poikiloderma, pachyony- REFERENCES chia, and chronic neutropenia. Ahmad W, Faiyaz ul Haque M, Brancolini V et al. (1998) A second challenge awaiting the reclassification of associated with a mutation in the human hairless gene. Science inherited hair disorders is the need to better understand the 279:720–4 pathophysiological relationships between similar or identical Ahmad W, Ratterree MS, Panteleyev AA et al. (2002) Atrichia with papular phenotypes resulting from mutations affecting seemingly lesions resulting from mutations in the rhesus macaque (Macaca mulatta) distinctive biochemical pathways. We mentioned above the hairless gene. Lab Anim 36:61–7 importance of b-catenin signaling for normal hair growth Ali G, Chishti MS, Raza SI et al. (2007) A mutation in the lipase H (LIPH) gene underlie autosomal recessive hypotrichosis. Hum Genet 121: (Fuchs, 2007) and its relationship to P-cadherin, which is 319–25 defective in HJMD (Sprecher et al., 2001). P-cadherin is a Alkuraya FS (2010) Homozygosity mapping: one more tool in the clinical major component of adherens junctions and colocalizes with geneticist’s toolbox. Genet Med 12:236–9 the P2RY5 receptor, which is defective in LAH3 (Pasternack Ayub M, Basit S, Jelani M et al. (2009) A homozygous nonsense mutation et al., 2008). Recent data indicate that the VDR, which has in the human desmocollin-3 (DSC3) gene underlies hereditary hypo- been linked to the pathogenesis of APL (Skorija et al., 2005), trichosis and recurrent skin vesicles. Am J Hum Genet 85:515–20 costimulates b-catenin signaling (Larriba et al., 2007). On the Azeem Z, Jelani M, Naz G et al. (2008) Novel mutations in G protein-coupled receptor gene (P2RY5) in families with autosomal recessive hypotrichosis other , hairless, which interacts with VDR (Hsieh et al., (LAH3). Hum Genet 123:515–9 2003) and is defective in APL, was found to regulate the Ballabio A, Parenti G, Carrozzo R et al. (1987) Isolation and characterization expression of ornithine decarboxylase, as well as of an of a steroid sulfatase cDNA clone: genomic deletions in patients with X- inhibitor of WNT signaling (Thompson et al., 2006), which in chromosome-linked ichthyosis. Proc Natl Acad Sci USA 84:4519–23 turn controls the intracytoplasmic levels of b-catenin Basel-Vanagaite L, Attia R, Ishida-Yamamoto A et al. (2007) Autosomal (Figure 5). recessive ichthyosis with hypotrichosis caused by a mutation in ST14, As anticipated as functional relationships between systems encoding type II transmembrane serine protease matriptase. Am J Hum Genet 80:467–77 implicated in the pathogenesis of phenotypically related Basel-Vanagaite L, Sarig O, Hershkovitz D et al. (2009) RIN2 deficiency disorders can be, they will have to be delineated in details as results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS they point to common regulatory pathways easily targetable syndrome. Am J Hum Genet 85:254–63

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