Hairless Gene Research Articles

Atrichia with papular lesions resulting from mutations in the rhesus macaque (Macaca mulatta) hairless gene.

Atrichia with papular lesions (APL) is a rare form of hair loss with an autosomal recessive mode of inheritance that is characterized by the absence of normal hair follicles, and formation of intradermal cystic structures. Mutations in the hairless (hr) gene in mice and humans have been implicated in the development of this phenotype. Hairless is a putative transcription factor containing a single zinc-finger DNA binding domain, with restricted expression in brain and skin. Here, we describe the complete hr cDNA sequence from the rhesus macaque (Macaca mulatta) and report the identification of a compound heterozygous mutation in a hairless rhesus macaque born from unrelated parents. Cutaneous biopsy samples from the affected macaque revealed abnormalities, including the replacement of normal hair follicles with dermal cysts and comedones, reminiscent of the skin phenotype observed in hairless mice and humans with APL.

Clinical and Molecular Diagnostic Criteria of Congenital Atrichia with Papular Lesions

Congenital atrichia with papular lesions is a rare, autosomal recessive form of total alopecia and mutations in the hairless (hir) gene have been implicated in this disorder. Published estimates of the prevalence of this disorder remain surprisingly low considering pathogenetic mutations in hir have been found in distinct ethnicities around the world. Therefore, it is likely that congenital atrichia with papular lesions is far more common than previously thought and is often mistaken for its phenocopy, the putative autoimmune form of alopecia universalis. To clarify this discrepancy, we propose criteria for the clinical diagnosis of congenital atrichia with papular lesions. Among these is the novel report of the consistent observation of hypopigmented whitish streaks on the scalp surface of affected individuals. Additionally, we report the identification of a novel missense mutation in hir from a family of Arab Palestinian origin that exhibits the pathognomonic features of atrichia with papular lesions. Collectively, we anticipate that an increased recognition of this disorder will result in more accurate diagnosis and the sparing of unnecessarily treatment to patients.

The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor.

The mammalian hairless (hr) gene plays a critical role in the maintenance of hair growth. Although the hr gene has been identified, the biochemical function of its encoded protein (Hr) has remained obscure. Here, we show that Hr functions as a transcriptional corepressor for thyroid hormone receptors (TRs). We find that two independent regions of Hr mediate TR binding and that interaction requires a cluster of hydrophobic residues similar to the binding motifs proposed for nuclear receptor corepressors (N-CoR and SMRT). Similarly, we show that Hr binds to the same region of TR as known corepressors. We show that Hr interacts with histone deacetylases (HDACs) and is localized to matrix-associated deacetylase (MAD) bodies, indicating that the mechanism of Hr-mediated repression is likely through associated HDAC activity. Thus, Hr is a component of the corepressor machinery, and despite its lack of sequence identity with previously described corepressors, its mode of action is remarkably conserved. On the basis of its thyroid hormone-inducible and tissue- and developmental-specific expression, Hr likely defines a new class of nuclear receptor corepressors that serve a more specialized role than ubiquitous corepressors. The discovery that Hr is a corepressor provides a molecular basis for specific hair loss syndromes in both humans and mice.

Atrichia Caused by Mutations in the Vitamin D Receptor Gene is a Phenocopy of Generalized Atrichia Caused by Mutations in the Hairless Gene

Generalized atrichia with papules is a rare disorder characterized by loss of hair shortly after birth and development of cutaneous cysts. Mutations in the hairless gene (HR) cause this phenotype in both mouse and human. Here we present a case of atrichia with papules in a patient with a normal HAIRLESS gene but with mutations in both alleles of the VITAMIN D RECEPTOR. The patient exhibited vitamin D resistant rickets, which was confirmed by an absent response of her fibroblasts to 1,25-dihydroxyvitamin D3 in vitro. Similar to individuals with HAIRLESS mutations, her skin showed an absence of normal hair follicles and the presence of follicular remnants and cysts. The cyst epithelium contained keratin-15- and keratin-17-positive cells suggesting derivation from the hair follicle bulge and the presence of epithelial stem cells. Although hair loss has been reported in association with hereditary vitamin D resistant rickets, we now characterize this alopecia as clinically and pathologically indistinguishable from generalized atrichia with papules, which was previously thought to be caused only by mutations in HAIRLESS. These findings suggest that VDR and HR, which are both zinc finger proteins, may be in the same genetic pathway that controls postnatal cycling of the hair follicle.

Reduction of glial fibrillary acidic protein-immunoreactive astrocytes in some brain areas of old hairless rhino-j mice ( hr-rh-j)

Mutations in the hairless ( hr) gene of mice result in hair follicle and other epithelial defects. The hr gene is expressed at high levels in the brain where it probably participates in the survival and maintenance of some neuronal populations, but whether it also supports glial populations of the central nervous system has been not investigated. To clarify this, quantitative immunohistochemistry for astrocytes (glial fibrillary acidic protein (GFAP)) and microglial cells (CD11b macrophage antigen) was used in the brain of a mutant mouse strain, the hairless ( hr-rh-j) type, which carries the homozygous hr gene rhino mutation. The glial cell density was assessed in the cerebral cortex, hippocampus, striatum, hypothalamus and cerebellum of young (3 months) and old (9 months) hr-rh-j mice. No significant differences were found between young wild-type and hr-rh-j mice. The density of GFAP immunoreactive astrocytes normally increased as a function of age, but in older hr-rh-j mice there was a severe reduction ( P<0.01) in the striatum, hypothalamus, and hippocampus. Conversely, the microglial cells were insensible to aging or to hr-rh-j mutation. These results suggest that the hr gene is involved in the maintenance of the GFAP immunoreactive cells in some cerebral areas. Nevertheless, because these animals do not show any neurological signs, the functional significance of the present findings remains to be established.

Characterization of Mouse Frizzled-3 Expression in Hair Follicle Development and Identification of the Human Homolog in Keratinocytes

Frizzled genes encode a family of Wnt ligand receptors, which have a conserved cysteine-rich Wnt binding domain and include both transmembrane and secreted forms. Work by others has shown that experimental perturbation of Wnt signaling results in aberrant hair formation, hair growth, and hair structure. To date, however, there is no information on the contribution of individual Frizzled proteins to hair development. We now report that Frizzled-3 expression in skin is restricted to the epidermis and to the developing hair follicle. Northern analysis on total mouse skin mRNA revealed a single Frizzled-3 transcript of 3.7 kb. Reverse transcription-polymerase chain reaction and in situ hybridization analysis revealed Frizzled-3 expression in epidermal and hair follicle keratinocytes. Frizzled-3 transcripts are first detected in discrete foci in the developing epidermis of 13 d embryos and later in the hair follicle placodes of 15 d embryos, suggesting a role for this Frizzled isoform in follicle development. In 17 d embryos and 1 d old newborn mice Frizzled-3 expression is limited to suprabasal keratinocytes and is not seen in pelage follicles until 3 d postpartum. In 7 d old neonatal skin, Frizzled-3 is expressed throughout the epidermis and in the outer cell layers of hair follicles. We have also identified the mRNA encoding human Frizzled-3 in epidermal keratinocytes and in the HaCaT keratinocyte cell line. Human Frizzled-3 mRNA encodes a 666 amino acid protein with 97.8% identity to the mouse protein. The human Frizzled-3 gene was mapped using a radiation-hybrid cell line panel to the short arm of chromosome 8 between the markers WI-1172 and WI-8496 near the loci for the Hypotrichosis of Marie Unna and Hairless genes.

Protein Kinase C Is Involved in the Regulation of hairless mRNA Expression during Mouse Keratinocyte Differentiation

The hairless (hr) gene is a putative transcriptional factor whose mutations lead to hair loss in animals and humans. As a step toward understanding the role of the hr gene, we investigated the expression of hr mRNA in mouse keratinocyte differentiation. Treatment of mouse primary keratinocyte cultures with phorbol-12-myristate-13-acetate (PMA) reduced DNA synthesis and sequentially induced an up-regulation of p21Cip1/WAF1 (p21), hr and involucrin (inv) mRNAs in a time-dependent fashion, suggesting that an increase in hr gene expression is associated with keratinocyte differentiation. This up-regulation was blocked by the RNA synthesis inhibitor actinomycin D. However, an increase in hr mRNA, but not in inv mRNA, was seen in cells treated with the protein synthesis inhibitor cycloheximide, suggesting that new protein synthesis is involved in the suppression of hr transcription or in the degradation of hr mRNA in the steady state. The up-regulation of hr mRNA expression by PMA was blocked by the protein kinase C (PKC) inhibitor, GF109203X. These data indicate that PKC activation is involved in the up-regulation of hr mRNA expression during mouse keratinocyte differentiation.

The thymus of the hairless rhino-j (hr/rh-j) mice.

The hairless (hr) gene is expressed in a large number of tissues, primarily the skin, and a mutation in the hr gene is responsible for the typical cutaneous phenotype of hairless mice. Mutant hr mouse strains show immune defects involving especially T cells and macrophages, as well as an age-related immunodeficiency and an accelerated atrophy of the thymus. These data suggest that the hr mutation causes a defect of this organ, although hr transcripts have not been detected in fetal or adult mice thymus. The present study analyses the thymus of young (3 mo) and adult (9 mo) homozygous hr-rh-j mice (a strain of hairless mice) by means of structural techniques and immunohistochemistry to selectively identify thymic epithelial cells, dendritic cells, and macrophages. There were structural alterations in the thymus of both young and adult rh-rh-j mice, which were more severe in older animals. These alterations consisted of relative cortical atrophy, enlargement of blood vessels, proliferation of perivascular connective tissue, and the appearance of cysts. hr-rh-j mice also showed a decrease in the number of epithelial and dendritic cells, and macrophages. Taken together, present results strongly suggest degeneration and accelerated age-dependent regression of the thymus in hr-rh-j mice, which could explain at least in part the immune defects reported in hairless mouse strains.

Hairless is translocated to the nucleus via a novel bipartite nuclear localization signal and is associated with the nuclear matrix.

Hair follicle cycling is an exquisitely regulated and dynamic process consisting of phases of growth, regression and quiescence. The transitions between the phases are governed by a growing number of regulatory proteins, including transcription factors. The hairless (hr) gene encodes a putative transcription factor that is highly expressed in the skin, where it appears to be an essential regulator during the regression of the catagen hair follicle. In hairless mice, as well as humans with congenital atrichia, the absence of hr gene function initiates a premature and abnormal catagen due to a dysregulation of apoptosis and cell adhesion, and defects in the signaling required for hair follicle remodeling. Here, we report structure-function studies of the hairless gene product, in which we identify a novel bipartite nuclear localization signal (NLS) of the form KRA(X13) PKR. Deletion analysis of the mouse hr gene mapped the NLS to amino acid residues 409-427. Indirect immunofluorescence microscopy of cells transiently transfected with hairless-green fluorescent fusion proteins demonstrated that these amino acid residues are necessary and sufficient for nuclear localization. Furthermore, nuclear fractionation analysis revealed that the hr protein is associated with components of the nuclear matrix.

Patterns of Hairless ( hr) Gene Expression in Mouse Hair Follicle Morphogenesis and Cycling

The hr (hairless) gene encodes a putative transcription factor with restricted expression in the skin and brain. Mutations in the hr locus cause papular atrichia in humans and complete hair loss in mice and other mammals. To further elucidate the role of hr in skin biology, and to identify potential target cells for hr regulation, we studied hr mRNA localization during hair follicle (HF) morphogenesis and cycling in normal C57BL/6J mice. In situ hybridization revealed that hr expression was present in the suprabasal cell layers of the epidermis, whereas the basal and highly differentiated keratinocytes of the granular layer were hr-negative. During the early stages of HF morphogenesis, hr mRNA was detected in the developing hair peg. Later, it became concentrated in the HF infundibulum, in the HF matrix, and in the inner root sheath (IRS), whereas the dermal papilla (DP) and outer root sheath were consistently hr mRNA-negative. During catagen, hr gene expression gradually declined in the regressing IRS, shortly but dramatically increased in the zone of developing club hair, and became up-regulated in the epithelial cells adjacent to the DP. The co-localization of hr mRNA with the site of the morphological defects in mutant skin implicates hr as a key factor in regulating basic cellular processes during catagen, including club hair formation, maintenance of DP-epithelial integrity, IRS disintegration, and keratinocyte apoptosis in the HF matrix.

A distinct gene close to the hairless locus on chromosome 8p underlies hereditary Marie Unna type hypotrichosis in a German family.

Hypotrichosis of the Marie Unna type (HMU) is a rare autosomal dominant disorder characterized by male-pattern hair loss with childhood onset and anomalies of the hair shaft. We aimed to evaluate a number of chromosomal loci as possible candidate regions for HMU. A linkage analysis was performed in a large German family using microsatellite markers spanning candidate regions on chromosomes 8, 12 and 17. We found that the HMU locus maps to chromosomal region 8p21 in a 13.01-cM interval between markers D8S1145 and D8S1771. This interval harbours the hairless gene (HR). Mutational analysis of HR on the genomic and transcript levels revealed no pathogenic mutation. Our findings, together with a recent report of two unrelated families of Dutch and British origin, provide evidence for a hair growth regulatory gene distinct from HR in chromosomal region 8p21.

Androgenetic alopecia in heterozygous carriers of a mutation in the human hairless gene

Background: Androgenetic alopecia is considered to be genetically determined. Recently, a rare autosomal recessive form of hereditary alopecia, termed atrichia with papular lesions (APL), was found to result from mutations in the human hairless gene. Objective: Our aim was to assess the pattern of androgenetic alopecia in heterozygous carriers of a deleterious mutation in the human hairless gene. Methods: Healthy male second-degree relatives (n = 31) of patients affected with APL and belonging to a large consanguineous kindred were interviewed and given a Hamilton score of baldness. DNA was obtained from each subject and analyzed for the presence of a mutation in the human hairless gene known to affect this family. The age at onset and extent of baldness were compared in healthy homozygotes and heterozygous carriers of the mutation. Results: Statistical analysis of the results revealed no differences in age at onset and extent of androgenetic alopecia between the two groups of subjects. Conclusion: The present study reports the first attempt to characterize the phenotype of heterozygous carriers of a mutation in the human hairless gene. It indicates that the presence of a deleterious mutation in one allele of the hairless gene does not affect the pattern of androgenetic hair loss. (J Am Acad Dermatol 2000;42:978–82.)

Androgenetic alopecia in heterozygous carriers of a mutation in the human hairless gene

Background: Androgenetic alopecia is considered to be genetically determined. Recently, a rare autosomal recessive form of hereditary alopecia, termed atrichia with papular lesions (APL), was found to result from mutations in the human hairless gene. Objective: Our aim was to assess the pattern of androgenetic alopecia in heterozygous carriers of a deleterious mutation in the human hairless gene. Methods: Healthy male second-degree relatives (n = 31) of patients affected with APL and belonging to a large consanguineous kindred were interviewed and given a Hamilton score of baldness. DNA was obtained from each subject and analyzed for the presence of a mutation in the human hairless gene known to affect this family. The age at onset and extent of baldness were compared in healthy homozygotes and heterozygous carriers of the mutation. Results: Statistical analysis of the results revealed no differences in age at onset and extent of androgenetic alopecia between the two groups of subjects. Conclusion: The present study reports the first attempt to characterize the phenotype of heterozygous carriers of a mutation in the human hairless gene. It indicates that the presence of a deleterious mutation in one allele of the hairless gene does not affect the pattern of androgenetic hair loss. (J Am Acad Dermatol 2000;42:978–82.)

Locus of Dominant Hairless Gene(Ht) Causing Abnormal Hair and Keratinization Maps to Rat Chromosome 10.

The rat dominant hairless gene (Ht) of the WBN/Ila-Ht rat causes atrichosis in Ht/Ht and hypotrichosis in Ht/+. Furthermore the Ht/Ht shows signs of abnormal keratinization and almost all of the Ht/Ht die in an immature stage before weaning in the conventional environment. Ht/+ was affected by dermatitis caused by Staphylococcus aureus, suggesting that the gene Ht might involve defense mechanisms against infection. In this study, we performed the linkage analysis of the gene Ht by outcross with the Brown Norway rat in the SPF environment. Ninety-six backcross progeny of (BN x WBN/Ila-Ht/Ht) F1 x WBN/Ila-Ht/Ht were typed with microsatellite markers and the gene Ht was mapped on chromosome 10 between Asgr1 and Nos2 within the map distance of 6.2 cM.

The Molecular Basis of Congential Artrichia in Humans and Mice: Mutations in the Hairless Gene

Congenital atrichia is a form of total alopecia inherited in an autosomal recessive pattern. In individuals affected with this form of hair loss, hairs are typically absent from the scalp, and patients are nearly completely devoid of eyebrows, eyelashes, axillary and pubic hair, following shedding of the natural hair shortly after birth. We have recently linked this disorder to the chromosomal region 8p12, and cloned the human hairless gene, which resides within this interval. We have identified several mutations in the hairless gene in atrichia families from around the world. In hairless mice, the hair matrix cells appear to undergo a premature and massive apoptosis, together with a concomitant decline in Bcl-2 expression, a loss of NCAM positivity, and a disconnection with the overlying epithelial sheath essential for the movement of the dermal papilla. As a consequence, the hair bulb and dermal papilla remain stranded in the dermis, and indispensible messages between the dermal papilla and stem cells in the bulge are not transmitted, so no further hair growth occurs. These findings suggest that the hairless gene product may play a crucial role in maintaining the delicate balance between cell proliferation, differentiation and apoptosis in the hair follicle, as well as in the interfollicular epidermis.

Novel Hairless Mutations in Two Kindreds with Autosomal Recessive Papular Atrichia

Papular atrichia is an autosomal recessive disorder characterized clinically by the occurrence of universal congenital alopecia and disseminated papular lesions. Recently, mutations in the human hairless (HR) gene have been reported in Irish and Arab Palestinian families with papular atrichia. We have studied two further kindreds with this clinical phenotype from other ethnic backgrounds. For mutation detection the complete coding region as well as exon-intron boundaries of the HR gene were sequenced. The first family is a Mexican family with clinically typical papular atrichia. Sequencing identified a homozygous deletion of 4 bp in exon 7 (2001delCCAG) leading to a premature stop codon in exon 8. The second family is a South Tyrolian family with affected individuals showing papular atrichia and retardation of bone age during childhood. All affected individuals were identified as homozygous for an A-->G transition at nucleotide position 2909 (exon 14) leading to an amino acid change of asparagine to serine in codon 970 (Asn970Ser). These data provide further evidence for the involvement of hairless mutations in papular atrichia. In addition, these findings suggest that the hairless protein is not only involved in hair development but also in the process of ossification during development.

The Abruptex Mutations of Notch Disrupt the Establishment of Proneural Clusters in Drosophila

The receptor encoded by the Notch gene plays a central role in preventing cells from making decisions about their fates until appropriate signals are present. This function of Notch requires the product of the Suppressor of Hairless gene. Loss of either Notch or Suppressor of Hairless function results in cells making premature and incorrect cell fate decisions, whilst increases in Notch signalling prevent cells from making these decisions. Here we find that the proneural clusters are not established correctly in certain Abruptex mutations of Notch and this failure to establish proneural clusters correctly is not due to increased Notch signalling during lateral inhibition. In addition we show that the overexpression of certain dominant negative Notch molecules can disrupt the initiation of proneural cluster development in a manner similar to the Abruptex mutants.

The hairless gene of the mouse: relationship of phenotypic effects with expression profile and genotype.

Various mutations of the hairless (hr) gene of mice result in hair loss and other integument defects. To examine the role of the hr gene in mouse development, the expression profile of hr has been determined by in situ hybridisation and correlated to the nature of genetic changes and morphological abnormalities in different mutant animals. Four variant alleles have been characterised at the molecular level. hr/hr mice produce reduced, but significant, levels of hr mRNA whereas other alleles contain mutations which would be expected to preclude the synthesis of functional product, demonstrating a correlation between allelic variation at the hr locus and phenotypic severity. hr expression was shown to be widespread and temporally regulated. It was identified in novel tissues such as cartilage, developing tooth, inner ear, retina, and colon as well as in skin and brain. Analysis of mice homozygous for the rhino allele of hairless revealed that, although no morphological defects were detectable in many tissues normally expressing hr, previously undescribed abnormalities were present in several tissues including inner ear, retina, and colon. These findings indicate that the hairless gene product plays a wider role in development than previously suspected. Dev Dyn 1999;216:113-126.

Of hairless mice and men: the genetic basis of congenital alopecia universalis/congenital atrichia.

Mouse models of human diseases help identify gene defects. The methods of homozygosity mapping and mouse/human homology to identify genes are reviewed. The genotype/phenotype correlation in two clinical entities with mutations in the human hairless gene are discussed. The example of the hairless mouse's contribution to our knowledge of hereditary alopecia is used, and the utility of consanguineous families for genetic studies is highlighted. Mutations in the human homolog of the mouse hairless gene lead to congenital alopecia universalis and atrichia with papules. A mouse model of congenital alopecia has led to understanding the molecular basis of at least one type of severe human alopecia.

The hairless gene of the mouse: Relationship of phenotypic effects with expression profile and genotype

Various mutations of the hairless (hr) gene of mice result in hair loss and other integument defects. To examine the role of the hr gene in mouse development, the expression profile of hr has been determined by in situ hybridisation and correlated to the nature of genetic changes and morphological abnormalities in different mutant animals. Four variant alleles have been characterised at the molecular level. hr/hr mice produce reduced, but significant, levels of hr mRNA whereas other alleles contain mutations which would be expected to preclude the synthesis of functional product, demonstrating a correlation between allelic variation at the hr locus and phenotypic severity. hr expression was shown to be widespread and temporally regulated. It was identified in novel tissues such as cartilage, developing tooth, inner ear, retina, and colon as well as in skin and brain. Analysis of mice homozygous for the rhino allele of hairless revealed that, although no morphological defects were detectable in many tissues normally expressing hr, previously undescribed abnormalities were present in several tissues including inner ear, retina, and colon. These findings indicate that the hairless gene product plays a wider role in development than previously suspected. Dev Dyn 1999;216:113–126. © 1999 Wiley-Liss, Inc.