Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Ther Nucleic Acids ; 18: 465-475, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31670143

RESUMO

Dystrophic epidermolysis bullosa (DEB) is a devastating blistering disease affecting skin and mucous membranes. It is caused by pathogenic variants in the COL7A1 gene encoding type VII collagen, and can be inherited dominantly or recessively. Recently, promising proof-of-principle has been shown for antisense oligonucleotide (AON)-mediated exon skipping as a therapeutic approach for DEB. However, the precise phenotypic effect to be anticipated from exon skipping, and which patient groups could benefit, is not yet clear. To answer these questions, we studied new clinical and molecular data on seven patients from the Dutch EB registry and reviewed the literature on COL7A1 exon skipping variants. We found that phenotypes associated with dominant exon skipping cannot be distinguished from phenotypes caused by other dominant DEB variants. Recessive exon skipping phenotypes are generally relatively mild in the spectrum of recessive DEB. Therefore, for dominant DEB, AON-mediated exon skipping is unlikely to ameliorate the phenotype. In contrast, the overall severity of phenotypes associated with recessive natural exon skipping pivots toward the milder end of the spectrum. Consequently, we anticipate AON-mediated exon skipping for recessive DEB caused by bi-allelic null variants should lead to a clinically relevant improvement of this devastating phenotype.

2.
Nat Commun ; 10(1): 2837, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253775

RESUMO

The diagnostic yield of exome and genome sequencing remains low (8-70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show that this unbiased method, which does not rely upon specific knowledge on individual genes, is effective in both identifying previously unknown disease gene associations, and flagging genes that have previously been incorrectly implicated in disease. GADO can be run on www.genenetwork.nl by supplying HPO-terms and a list of genes that contain candidate variants. Finally, applying GADO to a cohort of 61 patients for whom exome-sequencing analysis had not resulted in a genetic diagnosis, yields likely causative genes for ten cases.


Assuntos
Regulação da Expressão Gênica/fisiologia , Predisposição Genética para Doença , Análise de Sequência de RNA/métodos , Transcriptoma , Bases de Dados de Ácidos Nucleicos , Humanos , Modelos Genéticos , Análise de Componente Principal , Software , Interface Usuário-Computador
3.
Exp Dermatol ; 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30019435

RESUMO

Human skin graft mouse models are widely used to investigate and develop therapeutic strategies for the severe generalized form of recessive dystrophic epidermolysis bullosa (RDEB), which is caused by biallelic null mutations in COL7A1 and the complete absence of type VII collagen (C7). Most therapeutic approaches are focused on reintroducing C7. Therefore, C7 and anchoring fibrils are widely used as readouts in therapeutic research with skin graft models. In this study, we investigated the expression pattern of human and murine C7 in a grafting model, in which human skin is reconstituted out of in vitro cultured keratinocytes and fibroblasts. The model revealed that murine C7 was deposited in both human healthy control and RDEB skin grafts. Moreover, we found that murine C7 is able to form anchoring fibrils in human grafts. Therefore, we advocate the use of human-specific antibodies when assessing the reintroduction of C7 using RDEB skin graft mouse models.

5.
PLoS One ; 13(2): e0192994, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29470523

RESUMO

Revertant mosaicism, or "natural gene therapy", is the phenomenon in which germline mutations are corrected by somatic events. In recent years, revertant mosaicism has been identified in all major types of epidermolysis bullosa, the group of heritable blistering disorders caused by mutations in the genes encoding epidermal adhesion proteins. Moreover, revertant mosaicism appears to be present in all patients with a specific subtype of recessive epidermolysis bullosa. We therefore hypothesized that revertant mosaicism should be expected at least in all patients with recessive forms of epidermolysis bullosa. Naturally corrected, patient-own cells are of extreme interest for their promising therapeutic potential, and their presence in all patients would open exciting, new treatment perspectives to those patients. To test our hypothesis, we determined the probability that single nucleotide reversions occur in patients' skin using a mathematical developmental model. According to our model, reverse mutations are expected to occur frequently (estimated 216x) in each patient's skin. Reverse mutations should, however, occur early in embryogenesis to be able to drive the emergence of recognizable revertant patches, which is expected to occur in only one per ~10,000 patients. This underestimate, compared to our clinical observations, can be explained by the "late-but-fitter revertant cell" hypothesis: reverse mutations arise at later stages of development, but provide revertant cells with a selective growth advantage in vivo that drives the development of recognizable healthy skin patches. Our results can be extrapolated to any other organ with stem cell division numbers comparable to skin, which may offer novel future therapeutic options for other genetic conditions if these revertant cells can be identified and isolated.


Assuntos
Epidermólise Bolhosa/genética , Epidermólise Bolhosa/fisiopatologia , Queratinócitos/citologia , Modelos Biológicos , Mosaicismo , Mutação , Polimorfismo de Nucleotídeo Único , Idoso , Autoantígenos/genética , Proliferação de Células/genética , Criança , Epidermólise Bolhosa/embriologia , Epidermólise Bolhosa/patologia , Mutação em Linhagem Germinativa , Humanos , Queratinócitos/patologia , Queratinócitos/fisiologia , Masculino , Pessoa de Meia-Idade , Colágenos não Fibrilares/genética , Pele/crescimento & desenvolvimento , Pele/patologia , Pele/fisiopatologia , Células-Tronco
6.
Circ Cardiovasc Genet ; 10(4)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28790152

RESUMO

BACKGROUND: Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies. METHODS AND RESULTS: Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy. CONCLUSIONS: Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations but with a more benign course.


Assuntos
Cardiopatias/genética , Lamina Tipo A/genética , Adulto , Núcleo Celular/patologia , Núcleo Celular/ultraestrutura , Estudos de Coortes , Eletrocardiografia , Feminino , Efeito Fundador , Haplótipos , Cardiopatias/mortalidade , Cardiopatias/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Desequilíbrio de Ligação , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Membrana Nuclear/patologia , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Sarcômeros/fisiologia , Análise de Sequência de DNA
8.
Exp Dermatol ; 26(1): 3-10, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27376675

RESUMO

Genetic disorders affecting the skin, genodermatoses, constitute a large and heterogeneous group of diseases, for which treatment is generally limited to management of symptoms. RNA-based therapies are emerging as a powerful tool to treat genodermatoses. In this review, we discuss in detail RNA splicing modulation by antisense oligonucleotides and RNA trans-splicing, transcript replacement and genome editing by in vitro-transcribed mRNAs, and gene knockdown by small interfering RNA and antisense oligonucleotides. We present the current state of these therapeutic approaches and critically discuss their opportunities, limitations and the challenges that remain to be solved. The aim of this review was to set the stage for the development of new and better therapies to improve the lives of patients and families affected by a genodermatosis.


Assuntos
Terapia Genética/métodos , RNA/uso terapêutico , Dermatopatias Genéticas/terapia , Animais , Técnicas de Silenciamento de Genes , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , RNA Mensageiro/uso terapêutico , Trans-Splicing
10.
Mol Ther Nucleic Acids ; 5(10): e379, 2016 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-27754488

RESUMO

The "generalized severe" form of recessive dystrophic epidermolysis bullosa (RDEB-gen sev) is caused by bi-allelic null mutations in COL7A1, encoding type VII collagen. The absence of type VII collagen leads to blistering of the skin and mucous membranes upon the slightest trauma. Because most patients carry exonic point mutations or small insertions/deletions, most exons of COL7A1 are in-frame, and low levels of type VII collagen already drastically improve the disease phenotype, this gene seems a perfect candidate for antisense oligonucleotide (AON)-mediated exon skipping. In this study, we examined the feasibility of AON-mediated exon skipping in vitro in primary cultured keratinocytes and fibroblasts, and systemically in vivo using a human skin-graft mouse model. We show that treatment with AONs designed against exon 105 leads to in-frame exon 105 skipping at the RNA level and restores type VII collagen protein production in vitro. Moreover, we demonstrate that systemic delivery in vivo induces de novo expression of type VII collagen in skin grafts generated from patient cells. Our data demonstrate strong proof-of-concept for AON-mediated exon skipping as a systemic therapeutic strategy for RDEB.

11.
JAMA Dermatol ; 152(10): 1137-1141, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27384765

RESUMO

Importance: Epidermolysis bullosa simplex (EBS) is a group of clinically and genetically diverse mechanobullous genodermatoses characterized by the fragility of skin and mucous membranes. Recently, mutations in EXPH5 encoding exophilin-5 (also known as Slac2-b, an effector protein involved in intracellular vesicle trafficking and exosome secretion) have been implicated in the pathophysiology of EBS. Herein, we report a novel homozygous nonsense mutation in EXPH5 responsible for an EBS subtype with mottled pigmentation. Objective: To identify the gene mutation(s) accountable for the mottled pigmentation phenotype in a patient with suspected inherited skin fragility disorder. Design, Setting, and Participant: Data for this case report were acquired in an outpatient clinic and concern a referral from the primary care physician to the national Center for Blistering Diseases in The Netherlands. Data were acquired and analyzed from 2014 to 2016. Main Outcomes and Measures: Clinical examination and investigation were performed of the molecular basis of patient's skin fragility and mottled pigmentation phenotype. Electron microscopy studies described the underlying abnormalities on an ultrastructural level. Results: The clinical phenotype is characterized by mild generalized skin fragility, trauma-induced skin blistering since infancy, and development of remarkable diffuse mottled pigmentation on the trunk and proximal extremities. Sequencing the complete set of genes associated with epidermolysis bullosa revealed a homozygous nonsense mutation in exon 6 of EXPH5: c.3917C>G, p.Ser1306*. Electron microscopy revealed disruption of keratin filament cytoskeleton and accumulation of melanosomes in a disordered distribution in the keratinocytes. Conclusions and Relevance: To our knowledge, the current study illustrates the first clinically well-documented, mottled pigmentation phenotype related to a novel EXPH5 mutation. In addition, by means of electron microscopy image analysis, it proposes a hypothesis for the pigmentary changes in this rare autosomal recessive EBS subtype. These findings expand the genetic and phenotypic spectrum of human inherited skin fragility disorders, and we propose the addition of EBS resulting from EXPH5 mutations to the EBS-mottled pigmentation subtype.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Códon sem Sentido/genética , Epidermólise Bolhosa Simples/diagnóstico , Epidermólise Bolhosa Simples/genética , Adulto , Biomarcadores/sangue , Consanguinidade , Éxons/genética , Feminino , Humanos , Fenótipo , Fatores de Risco
12.
Mol Ther ; 24(7): 1302-11, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27157667

RESUMO

Genetically evoked deficiency of collagen VII causes dystrophic epidermolysis bullosa (DEB)-a debilitating disease characterized by chronic skin fragility and progressive fibrosis. Removal of exons carrying frame-disrupting mutations can reinstate protein expression in genetic diseases. The therapeutic potential of this approach is critically dependent on gene, protein, and disease intrinsic factors. Naturally occurring exon skipping in COL7A1, translating collagen VII, suggests that skipping of exons containing disease-causing mutations may be feasible for the treatment of DEB. However, despite a primarily in-frame arrangement of exons in the COL7A1 gene, no general conclusion of the aptitude of exon skipping for DEB can be drawn, since regulation of collagen VII functionality is complex involving folding, intra- and intermolecular interactions. To directly address this, we deleted two conceptually important exons located at both ends of COL7A1, exon 13, containing recurrent mutations, and exon 105, predicted to impact folding. The resulting recombinantly expressed proteins showed conserved functionality in biochemical and in vitro assays. Injected into DEB mice, the proteins promoted skin stability. By demonstrating functionality of internally deleted collagen VII variants, our study provides support of targeted exon deletion or skipping as a potential therapy to treat a large number of individuals with DEB.


Assuntos
Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/genética , Éxons , Marcação de Genes , Deleção de Sequência , Processamento Alternativo , Animais , Adesão Celular/genética , Linhagem Celular , Movimento Celular/genética , Colágeno Tipo VII/química , Epidermólise Bolhosa Distrófica/metabolismo , Epidermólise Bolhosa Distrófica/patologia , Epidermólise Bolhosa Distrófica/terapia , Humanos , Camundongos , Oligonucleotídeos Antissenso/genética , Dobramento de Proteína , Estabilidade Proteica , Fases de Leitura , Pele/metabolismo , Relação Estrutura-Atividade
13.
JAMA Dermatol ; 152(5): 558-62, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26817667

RESUMO

IMPORTANCE: Epidermolysis bullosa (EB) is a group of mechanobullous genodermatoses characterized by the fragility of skin and mucous membranes. Mutations in the ITGA6 and ITGB4 genes, encoding the hemidesmosomal protein α6ß4-integrin, have been involved in the pathogenesis of EB. To date, the inheritance of these particular genes is known to be exclusively autosomal recessive. Herein, we report a novel heterozygous missense mutation in the ITGB4 gene exerting a dominant negative effect that cosegregates with the EB phenotype in an extended family. OBSERVATIONS: The clinical phenotype of affected individuals is primarily characterized by nail dystrophy and late onset of mild skin fragility and acral blistering. Some patients developed granulation tissue in the larynx, urethra, lacrimal duct, and external auditory canal. Sequencing the complete set of genes associated with EB revealed a heterozygous missense mutation in exon 5 of ITGB4: c.433G>T, p.Asp145Tyr. The mutation was found in the affected relatives and was not present in unaffected relatives and control DNA samples. CONCLUSIONS AND RELEVANCE: This study highlights, for the first time to our knowledge, the possibility of a dominant mode of inheritance for a missense ITGB4 mutation in EB, thus expanding the mutational database and genotype-phenotype correlation for this rare disease.


Assuntos
Epidermólise Bolhosa/genética , Integrina beta4/genética , Mutação de Sentido Incorreto , Doenças da Unha/genética , Epidermólise Bolhosa/patologia , Éxons/genética , Família , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Doenças da Unha/etiologia , Doenças da Unha/patologia , Fenótipo
14.
BMC Res Notes ; 8: 264, 2015 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-26111702

RESUMO

BACKGROUND: The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer. However, there is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families. We aimed to test whether previously identified genetic risk factors for pancreatic cancer modify the risk for pancreatic cancer in p16-Leiden germline mutation carriers. METHODS: Seven pancreatic cancer-associated SNPs were selected from the literature and were genotyped in a cohort of 185 p16-Leiden germline mutation carriers from 88 families, including 50 cases (median age 55 years) with pancreatic cancer and 135 controls (median age 64 years) without pancreatic cancer. Allelic odds ratios per SNP were calculated. RESULTS: No significant association with pancreatic cancer was found for any of the seven SNPs. CONCLUSIONS: Since genetic modifiers for developing melanoma have already been identified in CDKN2A mutation carriers, this study does not exclude that genetic modifiers do not play a role in the individual pancreatic cancer risk in this cohort of p16-Leiden germline mutation carriers. The search for these modifiers should therefore continue, because they can potentially facilitate more targeted pancreatic surveillance programs.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Síndrome do Nevo Displásico/genética , Mutação em Linhagem Germinativa , Melanoma/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Síndrome do Nevo Displásico/complicações , Síndrome do Nevo Displásico/patologia , Feminino , Heterozigoto , Humanos , Masculino , Melanoma/complicações , Melanoma/patologia , Pessoa de Meia-Idade , Países Baixos , Razão de Chances , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Linhagem , Fatores de Risco , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia
15.
J Invest Dermatol ; 134(8): 2097-2104, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24577406

RESUMO

Revertant mosaicism has been reported in several inherited diseases, including the genetic skin fragility disorder epidermolysis bullosa (EB). Here, we describe the largest cohort of seven patients with revertant mosaicism and dystrophic EB (DEB), associated with mutations in the COL7A1 gene, and determine the underlying molecular mechanisms. We show that revertant mosaicism occurs both in autosomal dominantly and recessively inherited DEB. We found that null mutations resulting in complete loss of collagen VII and severe disease, as well as missense or splice-site mutations associated with some preserved collagen VII function and a milder phenotype, were corrected by revertant mosaicism. The mutation, subtype, and severity of the disease are thus not decisive for the presence of revertant mosaicism. Although collagen VII is synthesized and secreted by both keratinocytes and fibroblasts, evidence for reversion was only found in keratinocytes. The reversion mechanisms included back mutations/mitotic recombinations in 70% of the cases and second-site mutations affecting splicing in 30%. We conclude that revertant mosaicism is more common than previously assumed in patients with DEB, and our findings will have implications for future therapeutic strategies using the patient's naturally corrected cells as a source for cell-based therapies.


Assuntos
Epidermólise Bolhosa Distrófica/genética , Terapia Genética , Adolescente , Adulto , Criança , Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/terapia , Imunofluorescência , Humanos , Pessoa de Meia-Idade , Mosaicismo , Mutação
16.
Eur J Hum Genet ; 22(8): 1002-11, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24169522

RESUMO

Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.


Assuntos
Contratura/genética , Retardo do Crescimento Fetal/genética , Proteínas de Membrana/genética , Metaloendopeptidases/genética , Mutação , Progéria/genética , Anormalidades da Pele/genética , Alelos , Substituição de Aminoácidos , Contratura/diagnóstico , Análise Mutacional de DNA , Éxons , Feminino , Retardo do Crescimento Fetal/diagnóstico , Efeito Fundador , Estudos de Associação Genética , Humanos , Íntrons , Masculino , Linhagem , Progéria/diagnóstico , Sítios de Splice de RNA , Anormalidades da Pele/diagnóstico
17.
Hum Mutat ; 34(12): 1597-605, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24014347

RESUMO

Microvillus inclusion disease (MVID) is one of the most severe congenital intestinal disorders and is characterized by neonatal secretory diarrhea and the inability to absorb nutrients from the intestinal lumen. MVID is associated with patient-, family-, and ancestry-unique mutations in the MYO5B gene, encoding the actin-based motor protein myosin Vb. Here, we review the MYO5B gene and all currently known MYO5B mutations and for the first time methodologically categorize these with regard to functional protein domains and recurrence in MYO7A associated with Usher syndrome and other myosins. We also review animal models for MVID and the latest data on functional studies related to the myosin Vb protein. To congregate existing and future information on MVID geno-/phenotypes and facilitate its quick and easy sharing among clinicians and researchers, we have constructed an online MOLGENIS-based international patient registry (www.MVID-central.org). This easily accessible database currently contains detailed information of 137 MVID patients together with reported clinical/phenotypic details and 41 unique MYO5B mutations, of which several unpublished. The future expansion and prospective nature of this registry is expected to improve disease diagnosis, prognosis, and genetic counseling.


Assuntos
Síndromes de Malabsorção/genética , Microvilosidades/patologia , Mucolipidoses/genética , Mutação , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Sistemas On-Line , Sistema de Registros , Animais , Modelos Animais de Doenças , Enterócitos/metabolismo , Enterócitos/patologia , Humanos , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/metabolismo , Microvilosidades/genética , Microvilosidades/metabolismo , Mucolipidoses/diagnóstico , Mucolipidoses/metabolismo , Cadeias Pesadas de Miosina/química , Cadeias Pesadas de Miosina/metabolismo , Miosina Tipo V/química , Miosina Tipo V/metabolismo , Miosinas/genética
18.
Arch Dermatol ; 148(2): 213-6, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22004882

RESUMO

BACKGROUND: Dystrophic epidermolysis bullosa is a genetic blistering disorder caused by mutations in the type VII collagen gene, COL7A1. In revertant mosaicism, germline mutations are corrected by somatic events resulting in a mosaic disease distribution. This "natural gene therapy" phenomenon long has been recognized in other forms of epidermolysis bullosa but only recently in dystrophic epidermolysis bullosa. OBSERVATIONS: We describe a 21-year-old man with recessive dystrophic epidermolysis bullosa carrying the homozygous c.6508C>T (p.Gln2170X) nonsense mutation who reported an unaffected skin patch on his neck where blisters never had occurred. Immunofluorescent type VII collagen staining was normal in 80% of the unaffected skin biopsy; however, it was strongly reduced in the affected skin. In the unaffected skin, the somatic nucleotide substitution c.6510G>T reverted the germline nonsense codon to tyrosine (p.Gln2170Tyr), thereby restoring functional protein production. CONCLUSIONS: Revertant mosaicism is considered rare in recessive dystrophic epidermolysis bullosa. However, it might be more common than previously anticipated because our patient is the third in whom revertant mosaicism was identified in a short period of time. The correction mechanism is different than that previously reported. Systematic examination of patients with recessive dystrophic epidermolysis bullosa, therefore, will likely reveal more patients with revertant patches. This is important because the natural gene therapy phenomenon may provide opportunities for revertant cell therapy.


Assuntos
Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/genética , Mosaicismo , Adulto , Códon sem Sentido , Colágeno Tipo VII/análise , Análise Mutacional de DNA , Epidermólise Bolhosa Distrófica/metabolismo , Homozigoto , Humanos , Masculino , Adulto Jovem
19.
Hum Mutat ; 32(10): 1100-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21681854

RESUMO

Dystrophic epidermolysis bullosa (DEB) is a heritable blistering disorder that can be inherited autosomal dominantly (DDEB) or recessively (RDEB) and covers a group of several distinctive phenotypes. A large number of unique COL7A1 mutations have been shown to underlie DEB. Although general genotype-phenotype correlation rules have emerged, many exceptions to these rules exist, compromising disease diagnosing and genetic counseling. We therefore constructed the International DEB Patient Registry (http://www.deb-central.org), aimed at worldwide collection and sharing of phenotypic and genotypic information on DEB. As of May 2011, this MOLGENIS-based registry contains detailed information on 508 published and 71 unpublished patients and their 388 unique COL7A1 mutations, and includes all combinations of mutations. The current registry RDEB versus DDEB ratio of 4:1, if compared to prevalence figures, suggests underreporting of DDEB in the literature. Thirty-eight percent of mutations stored introduce a premature termination codon (PTC) and 43% an amino acid change. Submission wizards allow users to quickly and easily share novel information. This registry will be of great help in disease diagnosing and genetic counseling and will lead to novel insights, especially in the rare phenotypes of which there is often lack of understanding. Altogether, this registry will greatly benefit the DEB patients.


Assuntos
Colágeno Tipo VII/genética , Bases de Dados de Ácidos Nucleicos , Epidermólise Bolhosa Distrófica/genética , Mutação , Sistema de Registros , Epidermólise Bolhosa Distrófica/epidemiologia , Estudos de Associação Genética , Genótipo , Humanos , Internet , Fenótipo , Sistema de Registros/normas , Sistema de Registros/estatística & dados numéricos , Ferramenta de Busca
20.
J Allergy Clin Immunol ; 127(3): 661-7, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21377035

RESUMO

BACKGROUND: IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. OBJECTIVE: To investigate the association between filaggrin loss-of-function mutations and peanut allergy. METHODS: Case-control study of 71 English, Dutch, and Irish oral food challenge-positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥ 8 mm and/or peanut-specific IgE ≥ 15 kUL(-1)) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. RESULTS: Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge-positive patients (P = 3.0 × 10(-6); odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 10(-5); odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis. CONCLUSION: Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.


Assuntos
Predisposição Genética para Doença , Proteínas de Filamentos Intermediários/genética , Hipersensibilidade a Amendoim/genética , Canadá , Estudos de Casos e Controles , Europa (Continente) , Estudos de Associação Genética , Variação Genética , Humanos , Hipersensibilidade Imediata , Irlanda , Países Baixos , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA