RESUMO
Congenital generalized hypertrichosis terminalis (CGHT) is a rare condition characterized by universal excessive growth of pigmented terminal hairs and often accompanied with gingival hyperplasia. In the present study, we describe three Han Chinese families with autosomal-dominant CGHT and a sporadic case with extreme CGHT and gingival hyperplasia. We first did a genome-wide linkage scan in a large four-generation family. Our parametric multipoint linkage analysis revealed a genetic locus for CGHT on chromosome 17q24.2-q24.3. Further two-point linkage and haplotyping with microsatellite markers from the same chromosome region confirmed the genetic mapping and showed in all the families a microdeletion within the critical region that was present in all affected individuals but not in unaffected family members. We then carried out copy-number analysis with the Affymetrix Genome-Wide Human SNP Array 6.0 and detected genomic microdeletions of different sizes and with different breakpoints in the three families. We validated these microdeletions by real-time quantitative PCR and confirmed their perfect cosegregation with the disease phenotype in the three families. In the sporadic case, however, we found a de novo microduplication. Two-color interphase FISH analysis demonstrated that the duplication was inverted. These copy-number variations (CNVs) shared a common genomic region in which CNV is not reported in the public database and was not detected in our 434 unrelated Han Chinese normal controls. Thus, pathogenic copy-number mutations on 17q24.2-q24.3 are responsible for CGHT with or without gingival hyperplasia. Our work identifies CGHT as a genomic disorder.
Assuntos
Cromossomos Humanos Par 17/genética , Dosagem de Genes , Hiperplasia Gengival/genética , Hipertricose/congênito , Hipertricose/genética , Mutação/genética , Adolescente , Adulto , Pré-Escolar , Mapeamento Cromossômico , Feminino , Ligação Genética , Genoma Humano , Haplótipos/genética , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Fatores de Transcrição SOX9/genéticaRESUMO
Kindler syndrome is an autosomal recessive genodermatosis characterized by acral blistering in neonates and diffuse, progressive poikiloderma in later life. Other clinical features include photosensitivity, premature skin ageing and severe periodontal disease. Two groups have recently shown that the molecular basis of Kindler syndrome is loss of a novel epidermal protein, kindlin-1, encoded by the gene KIND1. Two additional kindlin proteins, kindlin-2 and kindlin-3, have also been described. Kindlin-1 is considered to be a component in the linkage of the actin cytoskeleton to the extracellular matrix and as such is proposed to have both structural and cell-signalling functions. Kindler syndrome is therefore the first skin fragility syndrome due to disruption of the actin-extracellular matrix system.
Assuntos
Epidermólise Bolhosa Distrófica/genética , Proteínas da Matriz Extracelular/genética , Mutação , Síndrome de Rothmund-Thomson/genética , Actinas/metabolismo , Epidermólise Bolhosa Distrófica/metabolismo , Epidermólise Bolhosa Distrófica/patologia , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/metabolismo , Humanos , Proteínas de Membrana , Proteínas de Neoplasias , Doenças Periodontais/genética , Transtornos de Fotossensibilidade/genética , Síndrome de Rothmund-Thomson/metabolismo , Síndrome de Rothmund-Thomson/patologia , Envelhecimento da Pele/genética , SíndromeRESUMO
Evidence is now emerging for enhanced penetration of chemical solutes into uninvolved skin of atopic dermatitis patients. Along with the recent discovery of prevalent null mutations in the gene encoding filaggrin, a protein essential for stratum corneum formation, these data point to an innate epidermal-barrier defect in atopy.
Assuntos
Dermatite Atópica/metabolismo , Proteínas de Filamentos Intermediários/genética , Pele/metabolismo , Dermatite Atópica/genética , Proteínas Filagrinas , Humanos , Mutação , Permeabilidade , Polietilenoglicóis/farmacocinéticaAssuntos
Permeabilidade da Membrana Celular/fisiologia , Dermatite Atópica/fisiopatologia , Proteínas de Filamentos Intermediários/genética , Mutação/genética , Fenômenos Fisiológicos da Pele , Pele/fisiopatologia , Adulto , Estudos de Casos e Controles , Permeabilidade da Membrana Celular/genética , Dermatite Atópica/genética , Feminino , Proteínas Filagrinas , Genótipo , Humanos , Bicamadas Lipídicas , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/farmacocinética , Perda Insensível de Água/fisiologiaRESUMO
Pachyonychia congenita (PC) is a rare genodermatosis affecting the nails, skin, oral mucosae, larynx, hair, and teeth. Pathogenic mutations in keratins K6a or K16 are associated with the PC-1 phenotype whereas K6b and K17 mutations are associated with the PC-2 phenotype. Analysis of clinical, pathological, and genetic data from the literature and two research registries reveal that >97% of PC cases exhibit fingernail and toenail thickening, and painful plantar keratoderma. Prospective evaluation of 57 PC patients from 41 families revealed variable clinical findings: hyperhidrosis (79%), oral leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma (60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%), coarse or twisted hair (26%), early primary tooth loss (14%), and presence of natal or prenatal teeth (2%). Stratification of these data by keratin mutation confirmed the increased incidence of cyst formation and natal teeth among PC-2 patients, although cysts were more commonly seen in PC-1 than previously reported (25%-33%). Previously unreported clinical features of PC include development of painful oral and nipple lesions during breastfeeding, copious production of waxy material in ears, and inability to walk without an ambulatory aid (50%). Possible pathogenic mechanisms are discussed with respect to the clinicopathologic and genetic correlations observed.