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2.
Eur Respir J ; 53(3)2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30655285

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-von Willebrand factor (VWF) axis in CTEPH, including its relationship with disease severity, inflammation, ABO groups and ADAMTS13 genetic variants.ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED) (n=35), resolved pulmonary embolism (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS13-VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF multimeric size.Patients with CTEPH had decreased ADAMTS13 (adjusted ß -23.4%, 95% CI -30.9- -15.1%, p<0.001) and increased VWF levels (ß +75.5%, 95% CI 44.8-113%, p<0.001) compared to healthy controls. ADAMTS13 levels remained low after reversal of pulmonary hypertension by pulmonary endarterectomy surgery and were equally reduced in CTED. We identified a genetic variant near the ADAMTS13 gene associated with ADAMTS13 protein that accounted for ∼8% of the variation in levels.The ADAMTS13-VWF axis is dysregulated in CTEPH. This is unrelated to pulmonary hypertension, disease severity or markers of systemic inflammation and implicates the ADAMTS13-VWF axis in CTEPH pathobiology.

3.
Eur Respir J ; 53(1)2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30545973

RESUMO

Since 2000 there have been major advances in our understanding of the genetic and genomics of pulmonary arterial hypertension (PAH), although there remains much to discover. Based on existing knowledge, around 25-30% of patients diagnosed with idiopathic PAH have an underlying Mendelian genetic cause for their condition and should be classified as heritable PAH (HPAH). Here, we summarise the known genetic and genomic drivers of PAH, the insights these provide into pathobiology, and the opportunities afforded for development of novel therapeutic approaches. In addition, factors determining the incomplete penetrance observed in HPAH are discussed. The currently available approaches to genetic testing and counselling, and the impact of a genetic diagnosis on clinical management of the patient with PAH, are presented. Advances in DNA sequencing technology are rapidly expanding our ability to undertake genomic studies at scale in large cohorts. In the future, such studies will provide a more complete picture of the genetic contribution to PAH and, potentially, a molecular classification of this disease.

4.
Nat Commun ; 9(1): 5075, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30542056

RESUMO

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne.


Assuntos
Acne Vulgar/genética , Acne Vulgar/patologia , Predisposição Genética para Doença/genética , Folículo Piloso/crescimento & desenvolvimento , Feminino , Variação Genética/genética , Estudo de Associação Genômica Ampla , Infecções por Bactérias Gram-Positivas/microbiologia , Infecções por Bactérias Gram-Positivas/patologia , Humanos , Laminina/biossíntese , Laminina/genética , Masculino , Proteínas de Membrana/metabolismo , Propionibacterium acnes/crescimento & desenvolvimento , Semaforinas/genética , Pele/patologia , Proteínas Wnt/genética
5.
Circ Genom Precis Med ; 11(10): e002087, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30354297

RESUMO

BACKGROUND: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target. METHODS: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. RESULTS: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)-a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. CONCLUSIONS: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.

6.
Am J Med Genet B Neuropsychiatr Genet ; 177(7): 641-657, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30325587

RESUMO

Individuals with psychiatric disorders have elevated rates of autoimmune comorbidity and altered immune signaling. It is unclear whether these altered immunological states have a shared genetic basis with those psychiatric disorders. The present study sought to use existing summary-level data from previous genome-wide association studies to determine if commonly varying single nucleotide polymorphisms are shared between psychiatric and immune-related phenotypes. We estimated heritability and examined pair-wise genetic correlations using the linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics methods. Using LDSC, we observed significant genetic correlations between immune-related disorders and several psychiatric disorders, including anorexia nervosa, attention deficit-hyperactivity disorder, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia, smoking behavior, and Tourette syndrome. Loci significantly mediating genetic correlations were identified for schizophrenia when analytically paired with Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus, and ulcerative colitis. We report significantly correlated loci and highlight those containing genome-wide associations and candidate genes for respective disorders. We also used the LDSC method to characterize genetic correlations among the immune-related phenotypes. We discuss our findings in the context of relevant genetic and epidemiological literature, as well as the limitations and caveats of the study.

7.
Sci Transl Med ; 9(411)2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-29021166

RESUMO

Interleukin (IL)-36α, IL-36ß, and IL-36γ are innate mediators of acute epithelial inflammation. We sought to demonstrate that these cytokines are also required for the pathogenesis of plaque psoriasis, a common and chronic skin disorder, caused by abnormal T helper 17 (TH17) cell activation. To investigate this possibility, we first defined the genes that are induced by IL-36 cytokines in primary human keratinocytes. This enabled us to demonstrate a significant IL-36 signature among the transcripts that are up-regulated in plaque psoriasis and the susceptibility loci associated with the disease in genome-wide studies. Next, we investigated the impact of in vivo and ex vivo IL-36 receptor blockade using a neutralizing antibody or a recombinant antagonist. Both inhibitors had marked anti-inflammatory effects on psoriatic skin, demonstrated by statistically significant reductions in IL-17 expression, keratinocyte activation, and leukocyte infiltration. Finally, we explored the potential safety profile associated with IL-36 blockade by phenotyping 12 individuals carrying knockout mutations of the IL-36 receptor gene. We found that normal immune function was broadly preserved in these individuals, suggesting that IL-36 signaling inhibition would not substantially compromise host defenses. These observations, which integrate the results of transcriptomics and model system analysis, pave the way for early-stage clinical trials of IL-36 antagonists.


Assuntos
Interleucina-1/metabolismo , Psoríase/metabolismo , Células Cultivadas , Humanos , Inflamação/genética , Inflamação/metabolismo , Interleucina-1/genética , Interleucina-17/metabolismo , Queratinócitos/metabolismo , Psoríase/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Pele/metabolismo
8.
Hum Mol Genet ; 26(21): 4301-4313, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973304

RESUMO

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.


Assuntos
Psoríase/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Exoma , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único/genética , Psoríase/fisiopatologia , Fatores de Risco , TYK2 Quinase/genética , TYK2 Quinase/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Sequenciamento Completo do Exoma
9.
Nat Commun ; 8(1): 303, 2017 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-28827725

RESUMO

Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations across multiple generations. Using exome sequences from 3222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10-8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10-6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germ-line mutation rate. We find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5' CCG 3' to 5' CTG 3' context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.Estimates of human mutation rates differ substantially based on the approach. Here, the authors present a multi-generational estimate from the autozygous segment in a non-European population that gives insight into the contribution of post-zygotic mutations and population-specific mutational processes.


Assuntos
Genética Populacional/métodos , Genoma Humano/genética , Taxa de Mutação , Mutação , Exoma/genética , Mutação em Linhagem Germinativa , Heterozigoto , Homozigoto , Humanos , Polimorfismo Genético
10.
Hum Mutat ; 37(11): 1157-1161, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27492651

RESUMO

Hereditary spastic paraplegias (HSPs) are genetically and clinically heterogeneous axonopathies primarily affecting upper motor neurons and, in complex forms, additional neurons. Here, we report two families with distinct recessive mutations in TFG, previously suggested to cause HSP based on findings in a single small family with complex HSP. The first carried a homozygous c.317G>A (p.R106H) variant and presented with pure HSP. The second carried the same homozygous c.316C>T (p.R106C) variant previously reported and displayed a similarly complex phenotype including optic atrophy. Haplotyping and bisulfate sequencing revealed evidence for a c.316C>T founder allele, as well as for a c.316_317 mutation hotspot. Expression of mutant TFG proteins in cultured neurons revealed mitochondrial fragmentation, the extent of which correlated with clinical severity. Our findings confirm the causal nature of bi-allelic TFG mutations for HSP, broaden the clinical and mutational spectra, and suggest mitochondrial impairment to represent a pathomechanistic link to other neurodegenerative conditions.


Assuntos
Mutação de Sentido Incorreto , Proteínas/genética , Proteínas/metabolismo , Paraplegia Espástica Hereditária/patologia , Animais , Células Cultivadas , Feminino , Predisposição Genética para Doença , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos , Mitocôndrias/patologia , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Análise de Sequência de DNA , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/metabolismo
11.
J Invest Dermatol ; 136(11): 2251-2259, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27388993

RESUMO

Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , DNA/genética , Interleucina-1/biossíntese , Queratinócitos/metabolismo , Mutação , Psoríase/genética , Regulação para Cima , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Idoso , Autofagia , Linhagem Celular , Análise Mutacional de DNA , Feminino , Humanos , Interleucina-1/genética , Queratinócitos/patologia , Pessoa de Meia-Idade , Psoríase/metabolismo , Psoríase/patologia , Transdução de Sinais , Ativação Transcricional
12.
Am J Hum Genet ; 98(6): 1092-1100, 2016 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-27236921

RESUMO

Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10(-9); OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.


Assuntos
Bacteriemia/genética , Pneumonia Pneumocócica/genética , Polimorfismo Genético/genética , RNA Longo não Codificante/genética , Streptococcus pneumoniae/genética , Adolescente , Bacteriemia/microbiologia , Bacteriemia/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Quênia/epidemiologia , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/patologia , Fatores de Risco
13.
Nat Genet ; 48(5): 510-8, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26974007

RESUMO

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.


Assuntos
Colangite Esclerosante/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Pleiotropia Genética , Inflamação/genética , Psoríase/genética , Espondilite Anquilosante/genética , Teorema de Bayes , Doença Crônica , Comorbidade , Heterogeneidade Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Locos de Características Quantitativas
14.
Science ; 352(6284): 474-7, 2016 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-26940866

RESUMO

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.


Assuntos
Consanguinidade , Saúde , Histona-Lisina N-Metiltransferase/genética , Adulto , Análise Mutacional de DNA , Prescrições de Medicamentos , Exoma/genética , Feminino , Fertilidade , Técnicas de Inativação de Genes , Genes Letais , Loci Gênicos , Genoma Humano , Recombinação Homóloga , Homozigoto , Humanos , Masculino , Mães , Paquistão/etnologia , Fenótipo , Reino Unido
15.
Hum Mol Genet ; 25(9): 1836-45, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-26945007

RESUMO

Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2-encoded ERß expression in the MTC tumour. ERα and ERß form heterodimers binding DNA at specific oestrogen-responsive elements (EREs) to regulate gene transcription. ERß represses ERα-mediated activation of the ERE and the RET promoter contains three EREs. In vitro, we showed that ESR2 c.948delT results in unopposed ERα mediated increased cellular proliferation, activation of the ERE and increased RET expression. In vivo, immunostaining of CCH and MTC using an anti-RET antibody demonstrated increased RET expression. Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis.


Assuntos
Carcinoma Medular/congênito , Receptor beta de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Adulto , Carcinoma Medular/genética , Carcinoma Medular/metabolismo , Carcinoma Medular/patologia , Proliferação de Células , Suscetibilidade a Doenças , Genótipo , Humanos , Masculino , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Linhagem , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/patologia , Células Tumorais Cultivadas , Regulação para Cima , Adulto Jovem
16.
Hum Mutat ; 36(12): 1113-27, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26387786

RESUMO

Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG), and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance, and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus-specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools.


Assuntos
Hipertensão Pulmonar/genética , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/química , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Modelos Animais de Doenças , Estudos de Associação Genética , Aconselhamento Genético , Predisposição Genética para Doença , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/metabolismo , Família Multigênica , Mutação , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
17.
J Invest Dermatol ; 135(12): 2964-2970, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26203641

RESUMO

Caspase recruitment family member 14 (CARD14, also known as CARMA2), is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Gain-of-function CARD14 mutations have been documented in familial forms of psoriasis vulgaris (PV) and pityriasis rubra pilaris (PRP). More recent investigations have also implicated CARD14 in the pathogenesis of pustular psoriasis. Follow-up studies, however, have been limited, so that it is not clear to what extent CARD14 alleles account for the above conditions. Here, we sought to address this question by carrying out a systematic CARD14 analysis in an extended patient cohort (n=416). We observed no disease alleles in subjects with familial PV (n=159), erythrodermic psoriasis (n=23), acral pustular psoriasis (n=100), or sporadic PRP (n=29). Conversely, our analysis of 105 individuals with generalized pustular psoriasis (GPP) identified a low-frequency variant (p.Asp176His) that causes constitutive CARD14 oligomerization and shows a significant association with GPP in Asian populations (P=8.4×10(-5); odds ratio=6.4). These data indicate that the analysis of CARD14 mutations could help stratify pustular psoriasis cohorts but would be mostly uninformative in the context of psoriasis and sporadic PRP.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Guanilato Ciclase/genética , Proteínas de Membrana/genética , Mutação , Psoríase/genética , Feminino , Humanos , Masculino , NF-kappa B/fisiologia , Multimerização Proteica , Psoríase/etiologia , Recidiva
18.
Nat Commun ; 6: 7001, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25939698

RESUMO

Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (P<5 × 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Psoríase/genética , Estudo de Associação Genômica Ampla , Humanos , Proteínas I-kappa B/genética , Interleucina-17/metabolismo , Queratinócitos/metabolismo , Proteínas Nucleares/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo
19.
Circ Cardiovasc Genet ; 8(4): 572-581, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25963545

RESUMO

BACKGROUND: Adams-Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS. METHODS AND RESULTS: Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique NOTCH1 mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of NOTCH1-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring NOTCH1 extracellular domain mutations, we observed significant reduction of NOTCH1 expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized NOTCH1 missense constructs also revealed significant reduction in gene expression. Mutant NOTCH1 expression was associated with downregulation of the Notch target genes HEY1 and HES1, indicating that NOTCH1-related AOS arises through dysregulation of the Notch signaling pathway. CONCLUSIONS: These findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders.


Assuntos
Displasia Ectodérmica/genética , Predisposição Genética para Doença/genética , Haploinsuficiência , Cardiopatias Congênitas/genética , Deformidades Congênitas dos Membros/genética , Receptor Notch1/genética , Dermatoses do Couro Cabeludo/congênito , Adolescente , Adulto , Sequência de Bases , Criança , Exoma/genética , Saúde da Família , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Estrutura Terciária de Proteína , Receptor Notch1/química , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Dermatoses do Couro Cabeludo/genética , Análise de Sequência de DNA/métodos , Transdução de Sinais/genética , Adulto Jovem
20.
Cancer Discov ; 5(7): 723-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25873077

RESUMO

UNLABELLED: Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC. SIGNIFICANCE: Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease.


Assuntos
Carcinoma de Células Renais/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Mutação em Linhagem Germinativa , Neoplasias Renais/genética , Análise de Sequência de DNA/métodos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Renais/química , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Mutação de Sentido Incorreto , Linhagem
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