Asunto(s)
Cardiomiopatía Dilatada/genética , Epidermólisis Ampollosa Simple/genética , Distrofias Musculares/genética , Plectina/genética , Adulto , Edad de Inicio , Cardiomiopatía Dilatada/complicaciones , Epidermólisis Ampollosa Simple/complicaciones , Salud de la Familia , Femenino , Humanos , Masculino , Distrofias Musculares/complicaciones , Plectina/química , Estructura Terciaria de ProteínaRESUMEN
Dystrophic epidermolysis bullosa can be inherited in autosomal dominant and recessive forms, the former usually expressed as a milder phenotype, although mild forms of recessive dystrophic epidermolysis bullosa can occur. We present a patient who was found to be a compound heterozygote, inheriting a dominant mutation from his father and a recessive mutation from his mother, resulting in a clinically severe case of dystrophic epidermolysis bullosa. Mutations in the gene for collagen VII (COL7A1) have been documented in both types of dystrophic epidermolysis bullosa. Our patient has also been diagnosed with bilateral auditory neuropathy, a disorder coincidentally also mapped to a nearby gene on chromosome 3p21 (the transmembrane inner ear expressed gene, TMIE).
Asunto(s)
Nervio Coclear , Colágeno Tipo VII/genética , Sordera/genética , Epidermólisis Ampollosa Distrófica/genética , Mutación Puntual , Enfermedades del Nervio Vestibulococlear/genética , Preescolar , Implantes Cocleares , Sordera/terapia , Epidermólisis Ampollosa Distrófica/diagnóstico , Humanos , Masculino , Enfermedades del Nervio Vestibulococlear/diagnóstico , Enfermedades del Nervio Vestibulococlear/terapiaRESUMEN
Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, and is characterized by ectopic mineralization of elastic fibers of connective tissues. Since the identification of the ABCC6 gene (ATP-binding cassette family C member 6), which encodes a putative transmembrane transporter (ABCC6), as the site of mutations responsible for PXE, a number of researchers have disclosed mutations spanning the entire gene. An important advance in the ability to identify mutations has been the identification of two closely related pseudogenes and identifying sequence differences between the coding gene and the pseudogenes allowing accurate sequencing. In this review, the mutation spectrum in PXE is summarized and a strategy to optimize mutation detection in this difficult disorder is outlined.
RESUMEN
BACKGROUND: Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance-associated protein 6). OBJECTIVE: To investigate the mutation spectrum of ABCC6 and possible genotype-phenotype correlations. METHODS: Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high-performance liquid chromatography-based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed. RESULTS: In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease. CONCLUSIONS: This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.
Asunto(s)
Análisis Mutacional de ADN , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Seudoxantoma Elástico/genética , Seudoxantoma Elástico/patología , Alelos , Cromatografía Líquida de Alta Presión/métodos , Codón , Genes Recesivos , Genotipo , Humanos , Cooperación Internacional , Modelos Genéticos , Mutación , Mutación Missense , Fenotipo , Enfermedades de la Piel/genética , Enfermedades de la Piel/patologíaAsunto(s)
Epidermólisis Ampollosa , Terapia Genética/métodos , Diagnóstico Prenatal , Membrana Basal/fisiopatología , Membrana Basal/ultraestructura , Epidermólisis Ampollosa/clasificación , Epidermólisis Ampollosa/diagnóstico , Epidermólisis Ampollosa/genética , Epidermólisis Ampollosa/terapia , Femenino , Enfermedades Fetales/diagnóstico , Humanos , Masculino , Trasplante de Células Madre Mesenquimatosas , Embarazo , Diagnóstico Preimplantación , Piel/ultraestructura , Enfermedades Cutáneas Genéticas/diagnósticoRESUMEN
Epidermolysis bullosa simplex (EBS) is a mechano-bullous disorder characterized by intraepidermal blistering within the basal keratinocytes as a result of trauma to the skin. As part of the DNA diagnostics program, our laboratory has analyzed a cohort of 57 patients with the initial referral diagnosis of EBS. Among these patients, 18 were found to harbor heterozygous mutations in the keratin 5 or keratin 14 genes, KRT5 and KRT14, respectively, whereas in 14 cases, the disease was associated with mutations in both alleles of the plectin gene. Among the keratin mutations, 12 were distinct and six were novel, and in most cases there was no family history of a blistering disease. Prenatal diagnosis of eight pregnancies with keratin gene mutations, at risk for EBS either because one of the parents was affected (three cases) or history of a previously affected child as a result of a de novo mutation (five cases), predicted two fetuses being affected and six being normal. No recurrence of the de novo mutations in these pregnancies was disclosed. Collectively, the data suggest that a significant number of cases diagnosed as EBS are due to plectin mutations, and many cases result from de novo mutations in KRT5 and KRT14 genes. These findings have implications for genetic counseling and prenatal diagnosis for EBS.
Asunto(s)
Epidermólisis Ampollosa Simple/genética , Asesoramiento Genético , Queratinas/genética , Diagnóstico Prenatal , Estudios de Cohortes , Genotipo , Humanos , Proteínas de Filamentos Intermediarios/genética , Queratina-14 , Queratina-5 , Fenotipo , Plectina , RecurrenciaRESUMEN
Epidermolysis bullosa (EB) is a group of inherited disorders characterized by increased skin fragility, resulting in blisters and erosions after minor trauma. Mutations in 10 structural genes expressed in the cutaneous basement membrane zone have been reported. The DebRA Molecular Diagnostics Laboratory at Jefferson Medical College has performed 144 DNA-based prenatal diagnoses since 1993 in families at risk for recurrence of the most severe forms of EB, including the recessive dystrophic EB (RDEB), junctional EB (JEB), EB with pyloric atresia (EB-PA), and EB simplex (EBS). A mutation-detection strategy using either conformation-sensitive gel electrophoresis (CSGE) or denaturing high-performance liquid chromatography (dHPLC) scanning analysis, followed by nucleotide sequencing, was applied to most cases with DEB and to all JEB, EB-PA, and EBS families. For some RDEB families, linkage analysis was performed, either alone when the inheritance pattern was clear or in combination with one mutation. Among the 144 prenatal diagnoses, 63 were for RDEB, 69 for JEB, 6 for EB-PA, and 6 for EBS. Twenty-eight normal, 73 heterozygous carrier, and 28 affected RDEB, JEB, and EB-PA pregnancies were reported in these recessively inherited diseases. Two affected and four normal pregnancies were predicted in dominantly inherited EBS. Among the 144 pregnancies, 9 were terminated without confirmation, 13 cases were lost to follow-up, and 6 pregnancies are ongoing. There were 6 families with inconclusive results due either to recombination events between flanking markers, absence of informative markers for one allele, or lack of sample from the previously affected child. There were three discordant results, one that was explained by maternal contamination of the chorionic villus sample and two that were unresolved. Overall, the availability, relative ease, and over 98% success rate make molecular DNA-based prenatal diagnosis a viable option for EB families at risk.