Identification of a novel splice site mutation in the human hairless gene underlying atrichia with papular lesions

Atrichia with Papular Lesions (APL) is a rare autosomal recessive disorder characterized by complete hair loss that begins shortly after birth with the development of papular lesions on various regions of the body. Since the establishment of hairless (HR) gene mutations as the cause of this disorder, several patients previously assumed to suffer from alopecia universalis have been subsequently diagnosed with APL. In this study we have identified a novel splicing mutation, IVS8+2T-->G, in the hairless gene. This mutation most likely abolishes normal splicing of exon 8 and potentially leads to out-of-frame skipping of this exon and a downstream premature termination codon (PTC). Our findings contribute to the growing body of HR mutations implicated in APL and provide further evidence for the differentiation of APL from alopecia universalis.     

Atrichia with papular lesions resulting from a nonsense mutation within the human hairless gene.

Atrichia with papular lesions is a rare autosomal recessive form of alopecia characterized by hair loss soon after birth and the development during childhood of a diffuse papular rash. We have previously shown that this disorder results from a deleterious mutation in the human hairless gene, a gene also involved in the pathogenesis of a related but clinically distinct form of congenital alopecia, termed alopecia universalis congenita. In this report, we describe a novel nonsense mutation in exon 4 of the human hairless gene in a consanguineous kindred affected with atrichia with papular lesions. This report provides additional evidence for phenotypic heterogeneity among inherited atrichias and for an association between the papular rash of atrichia with papular lesions and nonsense mutations in the human hairless gene.     

A newly identified missense mutation of the HR gene is associated with a novel, unusual phenotype of Marie Unna Hereditary Hypotrichosis 1 including limb deformities

Marie Unna Hereditary Hypotrichosis 1 (MUHH1; OMIM 146550), a rare monogenic condition characterized by the development of sparse, twisted hair or complete hair loss, is the consequence of mutations located in the hairless (HR) gene. We have identified a 68-year-old Hungarian woman affected by alopecia universalis and limb deformities of all four extremities. Direct sequencing of the coding regions of the HR gene revealed a novel missense mutation in the third exon of the HR gene (c.974G/A, p.Gly325Asp). The affected family member carried the mutation in a heterozygous form, while the only available, clinically unaffected family member (the son of the patient) and the unrelated controls carried the wild type sequence. The association between the presence of HR gene mutations and the development of alopecia is well-established, however, further studies are needed to elucidate the putative role of this novel HR mutation in the development of limb deformities.     

Congenital atrichia with papular lesions resulting from novel mutations in human hairless gene in four consanguineous families

Congenital atrichia with papular lesions (APL; Mendelian Inheritance in Man no. 209500) is a rare form of irreversible alopecia that follows an autosomal recessive mode of inheritance. Patients with this form of alopecia show hair loss soon after birth with the development of papular lesions of keratin-filled cysts over the body. Several studies have reported sequence variants in the human hairless (HR) gene as the underlying cause of this disorder. In the present study, we have reported four consanguineous families showing features of APL. Genotyping using microsatellite markers showed mapping of all four families to the hairless (HR) gene on chromosome 8p21.1. Further, DNA sequence analysis of the HR gene revealed three novel mutations including two nonsense (p.Cys690X, p.Arg819X) and a missense (p.Pro1157Arg) in the four families.     

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

BACKGROUND: Mouse models of human diseases help identify gene defects. OBJECTIVE: 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. METHODS: 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. RESULTS: Mutations in the human homolog of the mouse hairless gene lead to congenital alopecia universalis and atrichia with papules. CONCLUSION: A mouse model of congenital alopecia has led to understanding the molecular basis of at least one type of severe human alopecia.     

Identification of a recurrent mutation in the human hairless gene underlying atrichia with papular lesions

Identification of mutations in the hairless (HR) gene in patients with atrichia with papular lesions (APL) has proven of critical importance, as it provides a basis for the differentiation between APL and alopecia universalis. The establishment of the diagnostic criteria for APL has triggered the identification of a large number of APL patients among those suspected to suffer from alopecia universalis. This advancement has resulted in the discovery of an increasing number of hairless mutations in both consanguineous and nonconsanguineous APL families. Here, we report the identification of a homozygous mutation, 3434delC, in an APL patient of Arab-Palestinian descent. The proband is a 23-year-old female with generalized scalp and body alopecia. To confirm the diagnosis of APL and to identify the specific mutation, we sequenced the hairless gene. Sequencing of all exons of the hairless gene revealed a homozygous frameshift mutation, 3434delC, in exon 18. Interestingly, the same mutation was previously identified in an Arab-Israeli family. Our data suggest that the 3434delC mutation most likely represents a founder mutation in this geographical region.     

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.     

Atrichia with papular lesions: a report of three novel human hairless gene mutations and a revision of diagnostic criteria

Atrichia with papular lesions is a rare autosomal recessive condition characterized by complete irreversible hair loss during the first months of life and papules that appear during early childhood. Atrichia with papular lesions is frequently misdiagnosed as alopecia universalis, despite increasing reports of its prevalence and the presence of well-defined diagnostic criteria. Most cases of atrichia with papular lesions have been reported in consanguineous families residing in small geographical regions, but the increasing number of sporadic cases of unrelated individuals suggests that atrichia with papular lesions is more common than previously thought. Mutations in the human hairless gene on chromosome 8p12 have been implicated in this disease. Here, we report two novel heterozygous mutations in an Australian family and a novel homozygous mutation in 2 Arab siblings. We also revise the diagnostic criteria for atrichia with papular lesions in order to clarify its uniqueness and distinguishing features from alopecia universalis.     

Atrichia with papular lesions resulting from a novel insertion mutation in the human hairless gene

BACKGROUND: Congenital atrichia with papular lesions is a rare, recessively inherited condition of total alopecia, characterized clinically by complete and irreversible hair loss, which begins shortly after birth with the development of the papular lesions of keratin-filled cysts over an extensive area of the body. Mutations in the human hairless (HR) gene have been implicated in the pathogenesis of this disorder. OBJECTIVE: To search for a mutation in human HR in a family with congenital atrichia. METHODS: Linkage analysis was carried out using genotyping markers closely linked to congenital atrichia locus on chromosome 8p12. Subsequently, human HR was sequenced to identify a disease-causing mutation. RESULTS: A novel 11 bp insertion mutation, G202 (InsCTTCCCCCAGG), in exon 2 of the hairless gene was identified in a Pakistani consanguineous family affected by congenital atrichia. The insertion results in the expansion of 11 bp tandem repeat, which introduces a translational frameshift leading to downstream premature termination codon. CONCLUSIONS: This mutation is the first insertion mutation identified in the coding sequence of human HR. This extends our knowledge of mutations in HR that define the pathogenic basis of this disease.     

Identification of a novel U2HR mutation c.14C>T in a Chinese patient with Marie Unna hereditary hypotrichosis

Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant form of non-syndromic hereditary alopecia. Recently, loss-of-function mutations of an inhibitory upstream open reading frame (ORF) in the human hairless gene (HR), named U2HR, have been identified in some patients with MUHH. We investigated a sporadic Chinese patient with MUHH and identified a novel mutation in U2HR, c.14C>T (p.T5M), which extends the mutation spectrum of U2HR mutations.     

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.     

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 (hr) gene have been implicated in this disorder. Published estimates of the prevalence of this disorder remain surprisingly low considering pathogenetic mutations in hr have been found in distinct populations around the world. Therefore, it is likely that congenital atrichia with papular lesions is more common than previously thought and is often mistaken for 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 hr 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.     

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.     

Evidence for pseudodominant inheritance of atrichia with papular lesions

Atrichia with papular lesions is a rare form of total alopecia, in which mutations in the hairless gene have been shown to underlie the phenotype. In the literature to date, atrichia with papular lesions has generally been reported to be inherited in an autosomal recessive manner. A few rare cases exist, however, in which parent-to-child transmission of atrichia with papular lesions has been documented. In this study, further investigations were carried out into the molecular basis of atrichia with papular lesions in a family with mother-to-son transmission by searching for mutations in the human hairless gene. Specific ally, we wanted to determine whether this case truly represented an example of dominantly inherited atrichia with papular lesions, or whether another mode of inheritance might be responsible for the disorder in this kindred. Pseudodominant inheritance, for example, occurs when an individual with a known recessive disorder has a clinically unaffected partner, but then unexpectedly gives birth to children who are affected with the same recessive disorder as the affected parent, and can easily be distinguished from classical dominant inheritance with molecular diagnosis and haplotype analysis. In the family reported here, we have determined that both the mother and son are, in fact, homozygous for a novel mutation in the hairless gene, R33X. We provide the first evidence for pseudodominant inheritance in atrichia with papular lesions, and at the same time extend our knowledge of pathogenetic mutations in the human hairless gene. Importantly, this information allows revisions in genetic counseling for risk of transmission for individuals in the family, previously impossible in the absence of knowing the genetic basis of atrichia with papular lesions in this unusual kindred.     

Atrichia with papular lesions resulting from compound heterozygous mutations in the hairless gene: A lesson for differential diagnosis of alopecia universalis

BACKGROUND: Atrichia with papular lesions (APL) is a rare, autosomal recessive form of total alopecia in which mutations in the hairless (HR) gene have been shown to underlie the phenotype. OBJECTIVE: We suspect that APL is actually much more common than previously believed. We sought to investigate whether APL might also be found among patients in small families, particularly those giving a history of (1) normal hair at birth, which was shed and never regrew, and (2) "alopecia universalis" that is recalcitrant to any treatment. METHODS: We identified a small family of German origin in which 2 of 4 siblings were affected and gave this clinical history. Direct sequence analysis of the HR gene in the nuclear family was performed. RESULTS: Mutation analysis revealed distinct mutations on each allele of the HR gene. This is the first demonstration of compound heterozygous mutations underlying APL. CONCLUSION: These findings support the hypothesis that APL can exist in small nonconsanguineous families and may be masquerading clinically as alopecia universalis. Accurate discrimination between APL and alopecia universalis should prevent unnecessary treatment of patients affected with APL.     

Mutations in the hairless gene underlie APL in three families of Pakistani origin

BACKGROUND: Atrichia with papular lesions (APL) (OMIM#209500) is a rare autosomal recessively inherited form of irreversible alopecia characterized by papular lesions of keratin-filled cysts on various regions of the body. Males and females are equally affected and present with a distinct pattern of total hair loss on scalp, axilla and body. It begins shortly after birth with the development of hair loss, and patients are normally devoid of eyelashes and eyebrows. Mutations in the hairless (HR) gene have been previously shown to be responsible for APL. OBJECTIVE: In this study, we studied the molecular basis of APL in three unrelated families of Pakistani origin. METHOD: Molecular analysis of the HR genes was performed on genomic DNA from probands and family members. RESULTS: DNA sequencing of the HR gene in family A revealed a novel homozygous 2bp deletion in exon 6 leading to a frameshift and a downstream premature termination codon in exon 8 (1782-83delAG). In family B, we identified a novel homozygous deletion of a G nucleotide at the exon 15-intron 15 boundary, termed 3097delG. Family C carries a previously reported missense mutation consisting of an A-to-G transition at nucleotide 276 resulting in the mutation N970S in exon 14. CONCLUSION: Two mutations identified in this study are novel mutations in the HR gene and extend the body of evidence implicating the hairless gene family in the pathogenesis of human skin disorders. The one previously reported mutation suggests it may represent a recurrent mutation, or alternatively, an allele that is widely dispersed around the world.     

Identification of a new mutation in the gene coding for hairless protein responsible for alopecia universalis: The importance of direct gene sequencing

Mutations in the gene HR coding for the hairless protein are associated with atrichia with papular lesions (APL), an autosomal recessive form of alopecia universalis that is characterized by generalized scalp and body atrichia with papular lesions. We here describe a South Italian family of ancient Albanian heritage. The full phenotype with complete atrichia was expressed in 2 siblings, whereas the parents and one sister were unaffected. Direct sequencing of the gene coding for the hairless protein allowed the identification of a new mutation in exon 17. Consistent with the recessive inheritance of the disease, both the siblings were homozygous for the mutation, whereas the parents and the unaffected sister where heterozygous. A relevant discrepancy with a haplotype linkage study is reported, stressing the importance of gene sequencing in genetic diagnosis and counseling because linkage studies can be biased by recombination events.     

The hairless gene in androgenetic alopecia: results of a systematic mutation screening and a family-based association approach

BACKGROUND: Genetic disposition and androgen dependence are important characteristics of the common patterned loss of scalp hair known as androgenetic alopecia (AGA). The genetic factors contributing to AGA are currently unknown. The human hairless gene (HR) has recently been cloned and mutations have been reported in families with autosomal recessive universal congenital alopecia and papular atrichia. The main feature of these disorders is persistent complete absence of hair at or shortly after birth. This suggests that HR is essential and specific for the development of hair. OBJECTIVES: To test the hypothesis that HR may be involved in AGA. METHODS: We systematically screened HR for genetic variability by means of single-strand conformation analysis (SSCA) in 46 unrelated men with AGA. To test for an involvement of HR in the development of AGA, seven common variants were genotyped in 61 families with 93 affected offspring. The results were analysed with the transmission/disequilibrium test (TDT). RESULTS: SSCA showed 15 single nucleotide substitutions: eight missense mutations, four silent mutations and three mutations in exon-flanking intronic sequences. TDT results showed a marginally significant association between AGA and variants 3379-29G/T (P = 0.024) and 2611-68C/T (P = 0.047). These results, however, did not remain significant after applying the conservative Bonferroni correction for multiple testing. CONCLUSIONS: Our results do not provide evidence for a strong involvement of HR in the development of AGA, although a minor role cannot be fully excluded.     

Molecular basis for the rhino Yurlovo (hrrhY) phenotype: severe skin abnormalities and female reproductive defects associated with an insertion in the hairless gene

In 1989, mice bearing mutations at the hr (hairless) locus were first proposed as a model for the human hair growth disorder papular atrichia, since in both these mice and in corresponding patients, a complete hair loss develops due to disintegration of the normal follicle structure into dermal cysts and so-called utriculi. Recently, the human hairless gene was characterized, and pathogenetic mutations were found to be associated with a recessively inherited form atrichia with papular lesions; however, the functions of hr gene remain unclear. Allelic mutations in the murine hairless gene represent a potentially powerful tool to elucidate the role of the hairless gene protein product in hair follicle physiology. In 1980, several naked animals were discovered in a breeding colony of B10.R109/Y mice maintained in the Laboratory of Experimental Biological Models (L.E.B.M., Yurlovo, Moscow District, Russia). By cross breeding with hairles HRS/J hr/hr mice, this mutation was shown to be allelic with hairless. Here, we describe the molecular basis of the hr^rhY mutation in mice, which consists of a 13 bp insertion in exon 16 of the hr gene. Histological evaluation of Yurlovo mouse skin revealed some differences as compared to the hairless and rhino mutations, with the formation of dermal megacysts being the most specific peculiarity of the Yurlovo mutation. These results, together with previous studies of hr^rhY/hr^rhY mutant mice, suggest that the rhino Yurlovo (hr^rhY) mutation represents a third and potentially more severe variation of the hairless phenotype.