1. Introduction
(HF) is a skin appendage which exists on the entire skin surface, except for palmoplantar and mucosal regions. During embryogenesis, HF development is operated through reciprocal interactions between skin epithelial cells and underlying dermal cells [1]. The first signal to induce HF formation is considered to originate from the dermal cells. The epithelial cells which receive the dermal signal lead to form a placode (Figure 1). Then a signal from the placode results in forming a dermal condensate just beneath the placode (Figure 1). Additional interaction between these structures induces the downgrowth of the placode and forms a hair germ, which is the source of epithelial components of the HF (Figure 2). The dermal condensate is gradually surrounded by the HF epithelium and becomes a dermal papilla. It has been shown that many signaling molecules, such as Wnt, ectodysplasin (Eda), bone morphogenic protein (Bmp), and sonic hedgehog (Shh), play crucial roles in the HF development [1]. After the HF is generated, it undergoes dynamic cell kinetics, known as the hair cycle, throughout postnatal life, which is composed of three phases: catagen (regressing) phase, telogen (resting) phase and anagen (growing) phase [2]. In human scalp HFs, duration of the catagen, telogen, and anagen phases are 1-2 weeks, 2-3 months, and 2-6 years, respectively. The hair cycle, which is an amazing ability of self-renewal, is maintained by the stem cell niche in bulge portion of the HF, as well as the dermal papilla [3, 4].
The anagen HF has a highly complex structure with several distinct cell layers (Figure 3). During the anagen phase, cells from the bulge portion migrate downward to matrix region, while making the outer root sheath (ORS). The matrix cells actively proliferate and differentiate into the hair shaft, the inner root sheath (IRS), and the companion layer of the HF (Figure 3) [4]. The hair shaft shares a common structural organization, in which a multicellular cortex is surrounded by a cuticular layer, occasionally with a medulla layer centrally located within the cortex. The hair shaft is strongly keratinized at the level of keratinizing zone, and forms a rigid structure (Figure 3). Growth of the hair shaft is molded and supported by the IRS, the companion layer, and the ORS. The IRS is composed of three distinct layers: the IRS cuticle, Huxley’s layer, and Henle’s layer (Figure 3).
2. Hair follicle
Recent advances in molecular genetics have led to the identification of numerous genes that are expressed in the HF. Furthermore, mutations in some of these genes have been shown to underlie hereditary hair diseases in humans [2]. Causative genes for the diseases encode various proteins with different functions, such as structural proteins, transcription factors, and signaling molecules. This chapter aims to update recent findings regarding the molecular basis of genetic hair diseases.
3. Keratin disorders
Keratins are one of the major structural components of the HF, and are largely divided into type I (acidic) and type II (neutral to basic) keratins. The type I and type II keratins undergo heterodimerization, which leads to form keratin intermediate filaments (KIFs) in the cytoplasm [5]. Based on the amino acid composition, keratins are further classified into two groups: epithelial (soft) keratins and hair (hard) keratins. As compared to the epithelial keratins, the hair keratins show higher sulfur content in their N- and C-terminus, which plays an important role in interacting with hair keratin-associated proteins via disulfide bindings [6, 7]. All the keratin proteins are composed of an N-terminal rod domain, a central rod domain, and a C-terminal tail domain. Importantly, the N-terminal and the C-terminal regions of the rod domain are highly conserved in amino acid sequences, which are called helix initiation motif (HIM) and helix termination motif (HTM), respectively (Figure 4). It is believed that the HIM and the HTM play essential roles in heterodimerization between the keratins. In humans, gene clusters for the type I and type II keratin genes are mapped on chromosomes 17q21 [8] and 12q13 [9], respectively. To date, a total of 54 functional keratin genes (28 type I and 26 type II) have been identified and characterized in humans. It has been shown that during differentiation of the HF, various keratin genes are abundantly and differentially expressed, and contribute to HF keratinization, leading to the formation of a rigid structure [10]. In general, epithelial keratins are mainly expressed in the ORS, the companion layer, the IRS, while hair keratins are predominantly expressed in the hair shaft. In addition, it has recently been reported that some epithelial keratins are expressed in the hair shaft medulla as well [11]. It is noteworthy that mutations in several keratin genes have been reported to underlie hereditary hair disorders in humans (Table 1).
disease | inheritance pattern | OMIM# | main symptoms | gene | protein, function |
Monilethrix | AD | 158000 | moniliform hair, perifollicular papules | KRT81 KRT83 KRT86 | K81 (basic hair keratin) K83 (basic hair keratin) K86 (basic hair keratin) |
Pure hair and nail ectodermal dysplasia | AR | 602032 | hypotrichosis, spoon nails | K85 (basic hair keratin) | |
Autosomal dominant woolly hair (ADWH)/ hypotrichosis | AD | 194300/613981 | WH/ hypotrichosis | KRT74 KRT71 | K74 (basic epithelial keratin) K71 (basic epithelial keratin) |
Monilethrix is characterized clinically by fragile scalp hair shafts and diffuse perifollicular papules with erythema. As the hair of affected individuals with monilethrix is easily broken, they frequently show sparse hair (hypotrichosis). In most cases, monilethrix shows an autosomal dominant inheritance pattern (MIM 158000), while autosomal recessive forms (MIM 252200) also exist. Under microscopy, the hair shaft of affected individuals with monilethrix dysplays a characteristic anomaly, known as beaded or moniliform hair, which shows periodic changes in hair diameter. As a result, the hair leads to the formation of nodes and internodes (Figure 5) [12]. Autosomal dominant form of the disease is caused by heterozygous mutations in
Pure hair and nail ectodermal dysplasia (PHNED; MIM 602032) is characterized by absent or sparse hair, as well as nail dystrophy [16]. Hairs of affected individuals with PHNED are short and thin, and perifollicular papules can also be observed. In addition, their nails typically show koilonychia (spoon nails). The disease can show either an autosomal dominant or recessive inheritance trait. The autosomal recessive form has been mapped to chromosome 17p12-q21.2 [17] and 12p11.1-q21.1 [18] which contain the type I and type II keratin gene clusters, respectively. Subsequently, homozygous mutations in
In addition to hair keratins, it has recently been reported that mutations in HF-specific epithelial keratin genes are associated with hereditary woolly hair (WH)/hypotrichosis. WH is defined as an abnormal variant of tightly curled hair and is considered to be a kind of hair growth deficiency [21]. There are both syndromic and non-syndromic forms of WH. The non-syndromic forms of WH can show either an autosomal-dominant (ADWH; MIM 194300) or -recessive (ARWH; MIM 278150) inheritance pattern. It is well-known that WH is frequently associated with hypotrichosis. Recently, heterozygous mutations in
4. Hereditary hair disorders resulting from disruption of cell-cell adhesion molecules
Similar to epidermis, the HF epithelium possess a number of cell-cell adhesion structures, such as desmosomes, corneodesmosomes, adherens junctions, gap junctions, and tight junctions, which play important roles in maintaining the structure and the function of the HF. It has been shown that disruption of any of these structures can result in hereditary hair disorders in humans (Table 2).
Desmosome is a critical structure for cell-cell adhesion in most epithelial tissues, including the HF. The major structural component of the desmosome is the desmosomal cadherin family, which is comprised of the desmogleins (DSGs) and desmocollins (DSCs). In humans, 4
disease | inheritance pattern | OMIM# | main symptoms | gene | protein, function |
Localized autosomal recessive hypotrichosis 1 (LAH1)/monilethrix | AR | 607903/ 252200 | hypotrichosis, moniliform hair, perifollicular papules | desmoglein 4 | |
Hypotrichosis and recurrent skin vesicles | AR | 613102 | Hypotrichosis, skin vesicles or keratosis pilaris | desmocollin 3 | |
Naxos disease | AR | 601214 | WH, PPK, right ventricular cardiomyopathy | junctional plakoglobin | |
Carvajal syndrome | AR | 605676 | WH, PPK, left ventricular cardiomyopathy | desmoplakin | |
Ectodermal dysplasia/skin fragility syndrome | AR | 604536 | Hypotrichosis, fragile skin, nail dystrophy | plakophilin 1 | |
Hypotrichosis simplex of the scalp | AD | 146520 | Scalp-limited hypotrichosis | corneodesmosin | |
Netherton syndrome | AR | 256500 | ichthyosiform erythroderma, atopic manifestation, bamboo hair | LEKTI (serine protease inhibitor) | |
Ichthyosis with hypotrichosis | AR | 610765 | ichthyosis, hypotrichosis | matriptase (serine protease) | |
Hypotrichosis with juvenile macular dystrophy | AR | 601553 | Hypotrichosis, weak eyesight | P-cadherin | |
Ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM) syndrome | AR | 225280 | Hypotrichosis, weak eyesight, ectrodactyly | P-cadherin | |
Hidrotic ectodermal dysplasia (Clouston syndrome) | AD | 129500 | hypotrichosis, PPK, nail dystrophy | connexin 30 | |
Keratitis ichthyosis deafness (KID) syndrome | AD | 148210 | vascularizing keratitis, sensorial deafness, erythrokeratoderma, hypotrichosis | GJB2 GJB6 | connexin 26 connexin 30 |
Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis | AR | 607626 | Hypotrichosis, ichthyosis, jaundice, hapatomegaly, | claudin 1 |
Corneodesmosome is a modified desmosome in the stratum corneum (SC) of the epidermis, and plays a crucial in the desquamation process. One of the major components of the corneodesmosome is corneodesmosin (CDSN). CDSN is secreted by cytoplasmic vesicles into the extracellular core of desmosomes, and is progressively proteolysed by several serine proteases, such as kallikrein-related peptidases, which leads to the loss of cell-cell adhesivity in the SC and causes desquamation [42]. CDSN is also expressed predominantly in the IRS of the HF, and thus is considered to be important for terminal differentiation, as well as subsequent degradation of the IRS [43]. In 2003, heterozygous nonsense mutations in the
E- and P-cadherins are classical cadherins which are a major component of adherens junctions in the HF. When the HF placode is formed during embryogenesis, the expression of E-cadherin is markedly downregulated, while P-cadherin is simultaneously upregulated, and prominant expression of P-cadherin persists in the proximal portion of the HF. This phenomenon, known as cadherin switching, is believed to be essential for the HF morphogenesis [50]. In addition, P-cadherin has recently been shown to be important for postnatal hair growth and cycling as well [51]. The critical role of these classical cadherins in the HF has been further supported by two hereditary diseases resulting from mutations in the P-cadherin gene (
Gap junction (GJ) is a specialized intercellular structure that provides a pathway for both metabolic and ionic coupling between adjacent cells and maintains tissue homeostasis [55]. Connexins (Cxs) are 4-pass transmembrane proteins and the major component of the GJs. Clouston syndrome (MIM 129500), also known as hidrotic ectodermal dysplasia, is an autosomal dominant condition characterized by hypotrichosis, nail dystrophy, and palmoplantar keratoderma. The disease is caused by mutations in
In addition to the cell-cell adhesion structures described above, tight junction (TJ) also exists in the HF epithelium and expression patterns of TJ-associated proteins in the HF have previously been characterized [61]. Disruption of
5. Hereditary hair disorders associated with transcription factors
During the past 20 years, numerous genes that are expressed in the HF have been identified, and various transcription factors have been shown to be involved in transcriptional regulation of these genes. Of these, p63 is one of the main transcription factors expressed in the HF. During the HF morphogenesis, p63 is abundantly expressed in the HF placode (Figure 13). In the postnatal stage, it is strongly expressed in the ORS and the matrix region of the HF (Figure 14). It has previously been reported that mutations in
disease | inheritance pattern | OMIM# | main symptoms | gene | Protein, function |
Ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC ) syndrome | AD | 604292 | hypotrichosis, ectrodactyly, cleft lip/palate, hypodontia | tumor protein p63 | |
Ankyloblepharon, ectodermal defects, and cleft lip/palate (AEC) syndrome | AD | 106260 | hypotrichosis, ankyloblepharon, skin erosion, cleft lip/palate, hypodontia | tumor protein p63 | |
Rapp-Hodgkin syndrome | AD | 129400 | hypotrichosis, cleft lip/palate, hypodontia | tumor protein p63 | |
T cell immunodeficiency, congenital alopecia, and nail dystrophy (human nude phenotype) | AR | 601705 | atrichia, nail dystrophy, T-cell immuodeficiency | Forkhead box N1 | |
Atrichia with papular lesions | AR | 209500 | atrichia, papules | Hair less (transcriptional corepressor) | |
Marie-Unna hereditary hypotrichosis | AD | 146550 | Hypotrichosis, wiry hair | Small peptide that regulates translation of the HR protein | |
Trichorhinophalangeal syndrome type I/type III | AD | 190350/190351 | Hypotrichosis, peer-shaped nose, brachydactyly, clinodactyly | Zing finger transcription factor | |
Hypotrichosis-lymphedema-telangiectasia syndrome | AD/AR | 607823 | Hypotrichosis, lymphedema, telangiectasia (easily visible blood vessels) | SRY-BOX 18 | |
Trichodontoosseous syndrome | AD | 190320 | WH, hypodontia, bone anomalies | Distal-less homeobox 3 |
FOXN1, also known as WHN, is a transcription factor expressed in the matrix and the hair shaft of the HF, and has been shown to regulate the expression of several hair keratin genes [67]. FOXN1 is expressed in not only the HF, but also in the nail units and thymus. Mutations in the
Hairless (
TRPS1 is a transcription factor with GATA-type and Ikaros-type zinc finger domains, which has been shown to be abundantly expressed in both epithelial and mesenchymal components in the developing mouse HFs [74]. Furthermore, it has recently been reported that Trps1 plays crucial roles in regulating the expression of several Wnt inhibitors and various transcription factors during vibrissa follicle morphogenesis in mice [75]. In humans, mutations in the
In addition to the transcription factors described above, several other members are also associated with hereditary hair diseases. For instance, both dominantly- and recessively-inherited mutations in
6. Hereditary hair disorders caused by disruption in signaling pathways
It has been shown via analyses using mice models that several signaling pathways play crucial roles in the HF morphogenesis and development. In humans, disruption of these signaling pathways has been demonstrated to underlie various hereditary hair disorders (Table 4). In addition, information obtained from the analysis of hereditary hair diseases has highlighted a novel signaling pathway that had not previously been known to play a role in the HF development.
disease | inheritance pattern | OMIM# | main symptoms | gene | protein, function |
Hypohidrotic ectodermal dysplasia | XR | 305100 | Hypotrichosis, hypohidrosis, hypodontia | EDA | ectodysplasin A1 (EDA-A1) |
AD | 129490 | EDAR EDARADD TRAF6 | EDA-A1 receptor EDAR-associated death domain TNF receptor-associated factor 6 | ||
AR | 224900 | EDAR EDARADD | EDA-A1 receptor EDAR-associated death domain | ||
Odontoonychodermal dysplasia | AR | 257980 | Hypotrichosis, hypodontia, nail dystrophy, PPK | WNT10A | Wnt ligand |
Generalized hereditary hypotrichosis simplex | AD | 605389 | hypotrichosis | APCDD1 | Wnt inhibitor |
Localized autosomal recessive hypotrichosis 2 (LAH2)/autosomal recessive woolly hair 2 (ARWH2) | AR | 604379 | WH, hypotrichosis | LIPH | phosphatidic acid-selective phospholipase A1α (PA-PLA1α) |
LAH3/ARWH1 | AR | 611452/278150 | WH, hypotrichosis | LPAR6 | LPA6 (LPA receptor) |
Inflammatory skin and bowel disease | AR | 614328 | erythema, diarrhea, WH | ADAM17 | Tumor necrosis factor converting enzyme (TACE) |
Hypohidrotic ectodermal dysplasia (HED), also known as Christ-Siemens-Touraine syndrome, is a rare genetic disease characterized by abnormal development of hair, teeth, and sweat glands. Most cases of HED show an X-linked recessive inheritance pattern (MIM 305100), while a minority of HED is inherited as either an autosomal dominant (MIM 129490) or an autosomal recessive trait (MIM 224900). During the last 15 years, the molecular basis for HED has gradually been disclosed. X-linked HED is caused by mutations in ectodysplasin (
Odontoonychodermal dysplasia (OODD; MIM 257980) is an autosomal recessive disease which is characterized by various ectodermal abnormalities including hypotrichosis, hypodontia, nail dystrophy, and palmoplantar keratoderma. It has recently been shown that OODD is caused by loss of function mutations in the
In addition to Wnt ligands, abnormal function of Wnt inhibitors has recently been shown to cause a hereditary hair disorder in humans. Generalized hypotrichosis simplex (GHS; MIM 605389) is an autosomal dominant non-syndromic hair disorder which is characterized by progressive loss of scalp and body hairs starting in the middle of the first decade of life and almost complete baldness by the third decade [90]. In several families with GHS, an identical heterozygous missense mutation (L9R) has been identified in
Recently, a signaling of lipid mediators has been shown to play essential roles in hair growth. About a decade ago, phosphatidic acid, has been demonstrated to promote hair growth in organ culture system, suggesting a potential role of lipids in hair growth [93]. Later on, it has been reported that mutations in lipase H (
The
7. Conclusions
To identify causative genes responsible for hereditary hair disorders, as well as to disclose the functional relationship between these genes, has provided precious information to better understand the complex mechanisms for the HF development and cycling in humans. It is highly expected that recently-established methods in molecular genetics, especially whole genome sequencing [103], will enable us to find additional causative genes for the diseases. These genes may be associated with not only rare hair disorders, but also determining the hair texture in healthy individuals and/or more common hair diseases, such as alopecia areata and androgenetic alopecia.
Acknowledgement
I appreciate Drs. Atsushi Fujimoto and Hiroki Fujikawa (Niigata University, Japan) for their assistance to make figures. This work was supported in part by the Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) to Y.S.
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