RESUMO
SERPINS comprise a large and functionally diverse family of serine protease inhibitors. Here, we report three unrelated families with loss-of-function mutations in SERPINB8 in association with an autosomal-recessive form of exfoliative ichthyosis. Whole-exome sequencing of affected individuals from a consanguineous Tunisian family and a large Israeli family revealed a homozygous frameshift mutation, c.947delA (p.Lys316Serfs(∗)90), and a nonsense mutation, c.850C>T (p.Arg284(∗)), respectively. These two mutations are located in the last exon of SERPINB8 and, hence, would not be expected to lead to nonsense-mediated decay of the mRNA; nonetheless, both mutations are predicted to lead to loss of the reactive site loop of SERPINB8, which is crucial for forming the SERPINB8-protease complex. Using Sanger sequencing, a homozygous missense mutation, c.2T>C (p.Met1?), predicted to result in an N-terminal truncated protein, was identified in an additional family from UAE. Histological analysis of a skin biopsy from an individual homozygous for the variant p.Arg284(∗) showed disadhesion of keratinocytes in the lower epidermal layers plus decreased SERPINB8 levels compared to control. In vitro studies utilizing siRNA-mediated knockdown of SERPINB8 in keratinocytes demonstrated that in the absence of the protein, there is a cell-cell adhesion defect, particularly when cells are subjected to mechanical stress. In addition, immunoblotting and immunostaining revealed an upregulation of desmosomal proteins. In conclusion, we report mutations in SERPINB8 that are associated with exfoliative ichthyosis and provide evidence that SERPINB8 contributes to the mechanical stability of intercellular adhesions in the epidermis.
Assuntos
Adesão Celular/genética , Ictiose/genética , Mutação/genética , Serpinas/genética , Códon sem Sentido/genética , Consanguinidade , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Genes Recessivos/genética , Homozigoto , Humanos , Lactente , Queratinócitos/metabolismo , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , TurquiaRESUMO
Omphaloliths are uncommon benign umbilical lesions caused by the accumulation of sebum and keratin into a stone-like concretion. Recognition of this entity can prevent unnecessary procedures and imaging studies for uncomplicated cases. We present three cases of omphaloliths from our department and review all 26 cases previously reported in the English literature with regard to modes of presentation, potential risk factors, complications, and treatment options to guide clinicians. The mean age at presentation was 48 years. Of the 29 cases, 17 (59%) were asymptomatic. Male patients presented at a younger age and were more likely to present with complications compared to females who presented at an older age with asymptomatic lesions (P=0.006). Features of patients described included dementia, hirsutism, a deep or narrow umbilicus, multiple nevi, obesity, and poor hygiene. Two patients developed overlying pyogenic granulomas. Removal of asymptomatic lesions was uncomplicated and done using forceps or following irrigation, with no recurrence. Complications, including localized abscesses and peritonitis, were associated in 41% of patients who were treated surgically; recurrence was noted in one patient. Removal of omphaloliths is recommended, once identified, to reduce risks of complications and patients should be encouraged to improve their personal hygiene.
Assuntos
Umbigo/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cálculos/patologia , Feminino , Humanos , Queratinas , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sebo , Fatores SexuaisRESUMO
Autosomal-recessive exfoliative ichthyosis presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of nonerythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma. Using whole-genome homozygosity mapping, candidate-gene analysis and deep sequencing, we have identified loss-of-function mutations in the gene for protease inhibitor cystatin A (CSTA) as the underlying genetic cause of exfoliative ichthyosis. We found two homozygous mutations, a splice-site and a nonsense mutation, in two consanguineous families of Bedouin and Turkish origin. Electron microscopy of skin biopsies from affected individuals revealed that the level of detachment occurs in the basal and lower suprabasal layers. In addition, in vitro modeling suggests that in the absence of cystatin A protein, there is a cell-cell adhesion defect in human keratinocytes that is particularly prominent when cells are subject to mechanical stress. We show here evidence of a key role for a protease inhibitor in epidermal adhesion within the lower layers of the human epidermis.
Assuntos
Cistatina A/genética , Ictiose/genética , Mutação , Inibidores de Proteases/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Adesão Celular , Epiderme/metabolismo , Saúde da Família , Feminino , Pé/patologia , Genoma , Homozigoto , Humanos , Masculino , Modelos Genéticos , Dados de Sequência Molecular , Linhagem , Homologia de Sequência de Aminoácidos , Estresse MecânicoRESUMO
Harlequin ichthyosis (HI) is a devastating autosomal recessive congenital skin disease. It has been vital to elucidate the biological importance of the protein ABCA12 in skin-barrier permeability, following the discovery that ABCA12 gene mutations can result in this rare disease. ATP-binding cassette transporter A12 (ABCA12) is a member of the subfamily of ATP-binding cassette transporters and functions to transport lipid glucosylceramides (GlcCer) to the extracellular space through lamellar granules (LGs). GlcCer are hydrolysed into hydroxyceramides extracellularly and constitute a portion of the extracellular lamellar membrane, lipid envelope and lamellar granules. In HI skin, loss of function of ABCA12 due to null mutations results in impaired lipid lamellar membrane formation in the cornified layer, leading to defective permeability of the skin barrier. In addition, abnormal lamellar granule formation (distorted shape, reduced in number or absent) could further cause aberrant production of LG-associated desquamation enzymes, which are likely to contribute to the impaired skin barrier in HI. This article reviews current opinions on the patho-mechanisms of ABCA12 action in HI and potential therapeutic interventions based on targeted molecular therapy and gene therapy strategies.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Ictiose Lamelar/genética , Mutação de Sentido Incorreto , Pele/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Humanos , Ictiose Lamelar/metabolismo , Metabolismo dos Lipídeos/genética , Pele/patologiaRESUMO
Glucocorticoids (GC) are the primary steroids that regulate inflammation and have been exploited therapeutically in inflammatory skin diseases. Despite the broad-spectrum therapeutic use of GC, the biochemical rationale for locally treating inflammatory skin conditions is poorly understood, as systemic GC production remains largely functional in these patients. GC synthesis has been well characterized in healthy skin, but the pathological consequence has not been examined. Here we show de novo GC synthesis, and GC receptor expression is dysfunctional in both nonlesional and lesional psoriatic skin. Use of GC receptor epidermal knockout mice with adrenalectomy allowed for the distinction between local (keratinocyte) and systemic GC activity. Compensation exhibited by adult GC receptor epidermal knockout mice demonstrated that keratinocyte-derived GC synthesis protected skin from topical phorbol 12-myristate 13-acetate-induced inflammatory assault. Thus, localized de novo GC synthesis in skin is essential for controlling inflammation, and loss of the GC pathway in psoriatic skin represents an additional pathological process in this complex inflammatory skin disease.
Assuntos
Regulação da Expressão Gênica , Queratinócitos/metabolismo , Psoríase/genética , RNA/genética , Receptores de Glucocorticoides/genética , Animais , Modelos Animais de Doenças , Epiderme/metabolismo , Epiderme/patologia , Humanos , Immunoblotting , Queratinócitos/patologia , Masculino , Camundongos , Camundongos Knockout , Psoríase/metabolismo , Psoríase/patologia , Radioimunoensaio , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Glucocorticoides/biossínteseRESUMO
OBJECTIVE: To assess the clinical outcomes of 45 cases of harlequin ichthyosis and review the underlying ABCA12 gene mutations in these patients. DESIGN: Multicenter, retrospective, questionnaire-based survey. SETTING: Dermatology research institute. PARTICIPANTS: Patients with harlequin ichthyosis for whom we had performed ABCA12 mutation analysis. MAIN OUTCOME MEASURES: Referring physicians were asked to complete a questionnaire using the patients' notes, detailing the clinical outcome of the affected child. In each case, the causative ABCA12 mutation was identified using standard polymerase chain reaction and sequencing techniques. RESULTS: Of the 45 cases, the ages of the survivors ranged from 10 months to 25 years, with an overall survival rate of 56%. Death usually occurred in the first 3 months and was attributed to sepsis and/or respiratory failure in 75% of cases. The early introduction of oral retinoids may improve survival, since 83% of those treated survived, whereas 76% who were not given retinoids died. Recurrent skin infections in infancy affected one-third of patients. Problems maintaining weight affected 44%. Three children developed an inflammatory arthritis, and developmental delay was reported in 32%. Mutation analysis revealed that 52% of survivors had compound heterozygous mutations, whereas all deaths were associated with homozygous mutations. CONCLUSIONS: Harlequin ichthyosis should be regarded as a severe chronic disease that is not invariably fatal. With improved neonatal care and probably the early introduction of oral retinoids, the number of survivors is increasing. Compound heterozygotes appear to have a survival advantage.