RESUMO
Cell adhesion and communication are interdependent aspects of cell behavior that are critical for morphogenesis and tissue architecture. In the skin, epidermal adhesion is mediated in part by specialized cell-cell junctions known as desmosomes, which are characterized by the presence of desmosomal cadherins, known as desmogleins and desmocollins. We identified a cadherin family member, desmoglein 4, which is expressed in the suprabasal epidermis and hair follicle. The essential role of desmoglein 4 in skin was established by identifying mutations in families with inherited hypotrichosis, as well as in the lanceolate hair mouse. We also show that DSG4 is an autoantigen in pemphigus vulgaris. Characterization of the phenotype of naturally occurring mutant mice revealed disruption of desmosomal adhesion and perturbations in keratinocyte behavior. We provide evidence that desmoglein 4 is a key mediator of keratinocyte cell adhesion in the hair follicle, where it coordinates the transition from proliferation to differentiation.
Assuntos
Caderinas/metabolismo , Adesão Celular/genética , Diferenciação Celular/genética , Proteínas do Citoesqueleto/metabolismo , Epiderme/embriologia , Folículo Piloso/embriologia , Hipertricose/metabolismo , Pênfigo/metabolismo , Animais , Caderinas/genética , Caderinas/imunologia , Mapeamento Cromossômico , Cromossomos Humanos Par 18/genética , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/imunologia , Análise Mutacional de DNA , Desmogleínas , Epiderme/metabolismo , Epiderme/patologia , Feminino , Folículo Piloso/metabolismo , Folículo Piloso/patologia , Humanos , Hipertricose/genética , Hipertricose/imunologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Mutantes , Microscopia Eletrônica , Dados de Sequência Molecular , Mutação/genética , Linhagem , Pênfigo/genética , Pênfigo/imunologia , FenótipoRESUMO
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.
Assuntos
Alopecia/genética , Alopecia/patologia , Proteínas/genética , Couro Cabeludo/patologia , Algoritmos , Alopecia/congênito , Criança , Análise Mutacional de DNA , Feminino , Humanos , Linhagem , Fatores de TranscriçãoRESUMO
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.
