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1.
J Hum Genet ; 64(7): 689-694, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31068678

RESUMO

Cathepsin C (CatC) is a cysteine protease involved in a variety of immune and inflammatory pathways such as activation of cytotoxicity of various immune cells. Homozygous or compound heterozygous variants in the CatC coding gene CTSC cause different conditions that have in common severe periodontitis. Periodontitis may occur as part of Papillon-Lefèvre syndrome (PLS; OMIM#245000) or Haim-Munk syndrome (HMS; OMIM#245010), or may present as an isolated finding named aggressive periodontitis (AP1; OMIM#170650). AP1 generally affects young children and results in destruction of the periodontal support of the primary dentition. In the present study we report exome sequencing of a three generation consanguineous Turkish family with a recessive form of early-onset AP1. We identified a novel homozygous missense variant in exon 2 of CTSC (NM_148170, c.G302C, p.Trp101Ser) predicted to disrupt protein structure and to be disease causing. This is the first described CTSC variant specific to the nonsyndromic AP1 form. Given the broad phenotypic spectrum associated with CTSC variants, reporting this novel variant gives new insights on genotype/phenotype correlations and might improve diagnosis of patients with early-onset AP1.

3.
Bioinformatics ; 35(21): 4394-4396, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30942877

RESUMO

SUMMARY: HLA*LA implements a new graph alignment model for human leukocyte antigen (HLA) type inference, based on the projection of linear alignments onto a variation graph. It enables accurate HLA type inference from whole-genome (99% accuracy) and whole-exome (93% accuracy) Illumina data; from long-read Oxford Nanopore and Pacific Biosciences data (98% accuracy for whole-genome and targeted data) and from genome assemblies. Computational requirements for a typical sample vary between 0.7 and 14 CPU hours per sample. AVAILABILITY AND IMPLEMENTATION: HLA*LA is implemented in C++ and Perl and freely available as a bioconda package or from https://github.com/DiltheyLab/HLA-LA (GPL v3). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

4.
Sci Rep ; 9(1): 895, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696890

RESUMO

The prognosis of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains unsatisfactory and, despite major advances in genomic studies, the biological mechanisms underlying chemoresistance are still poorly understood. We conducted for the first time a large-scale differential multi-omics investigation on DLBCL patient's samples in order to identify new biomarkers that could early identify patients at risk of R/R disease and to identify new targets that could determine chemorefractoriness. We compared a well-characterized cohort of R/R versus chemosensitive DLBCL patients by combining label-free quantitative proteomics and targeted RNA sequencing performed on the same tissues samples. The cross-section of both data levels allowed extracting a sub-list of 22 transcripts/proteins pairs whose expression levels significantly differed between the two groups of patients. In particular, we identified significant targets related to tumor metabolism (Hexokinase 3), microenvironment (IDO1, CXCL13), cancer cells proliferation, migration and invasion (S100 proteins) or BCR signaling pathway (CD79B). Overall, this study revealed several extremely promising biomarker candidates related to DLBCL chemorefractoriness and highlighted some new potential therapeutic drug targets. The complete datasets have been made publically available and should constitute a valuable resource for the future research.

5.
Am J Hum Genet ; 104(2): 319-330, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639322

RESUMO

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação Puntual , Fatores de Transcrição/genética , Alelos , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Camundongos , Síndrome , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
6.
PLoS Pathog ; 14(10): e1007368, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30335851

RESUMO

Infection with human BK polyomavirus, a small double-stranded DNA virus, potentially results in severe complications in immunocompromised patients. Here, we describe the in vivo variability and evolution of the BK polyomavirus by deep sequencing. Our data reveal the highest genomic evolutionary rate described in double-stranded DNA viruses, i.e., 10-3-10-5 substitutions per nucleotide site per year. High mutation rates in viruses allow their escape from immune surveillance and adaptation to new hosts. By combining mutational landscapes across viral genomes with in silico prediction of viral peptides, we demonstrate the presence of significantly more coding substitutions within predicted cognate HLA-C-bound viral peptides than outside. This finding suggests a role for HLA-C in antiviral immunity, perhaps through the action of killer cell immunoglobulin-like receptors. The present study provides a comprehensive view of viral evolution and immune escape in a DNA virus.

7.
Ann Rheum Dis ; 77(11): 1675-1687, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30030262

RESUMO

OBJECTIVES: The objective of the present study was to explain why two siblings carrying both the same homozygous pathogenic mutation for the autoinflammatory disease hyper IgD syndrome, show opposite phenotypes, that is, the first being asymptomatic, the second presenting all classical characteristics of the disease. METHODS: Where single omics (mainly exome) analysis fails to identify culprit genes/mutations in human complex diseases, multiomics analyses may provide solutions, although this has been seldom used in a clinical setting. Here we combine exome, transcriptome and proteome analyses to decipher at a molecular level, the phenotypic differences between the two siblings. RESULTS: This multiomics approach led to the identification of a single gene-STAT1-which harboured a rare missense variant and showed a significant overexpression of both mRNA and protein in the symptomatic versus the asymptomatic sister. This variant was shown to be of gain of function nature, involved in an increased activation of the Janus kinase/signal transducer and activator of transcription signalling (JAK/STAT) pathway, known to play a critical role in inflammatory diseases and for which specific biotherapies presently exist. Pathway analyses based on information from differentially expressed transcripts and proteins confirmed the central role of STAT1 in the proposed regulatory network leading to an increased inflammatory phenotype in the symptomatic sibling. CONCLUSIONS: This study demonstrates the power of a multiomics approach to uncover potential clinically actionable targets for a personalised therapy. In more general terms, we provide a proteogenomics analysis pipeline that takes advantage of subject-specific genomic and transcriptomic information to improve protein identification and hence advance individualised medicine.

8.
Dev Cell ; 45(1): 33-52.e12, 2018 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-29634935

RESUMO

Metastatic seeding is driven by cell-intrinsic and environmental cues, yet the contribution of biomechanics is poorly known. We aim to elucidate the impact of blood flow on the arrest and the extravasation of circulating tumor cells (CTCs) in vivo. Using the zebrafish embryo, we show that arrest of CTCs occurs in vessels with favorable flow profiles where flow forces control the adhesion efficacy of CTCs to the endothelium. We biophysically identified the threshold values of flow and adhesion forces allowing successful arrest of CTCs. In addition, flow forces fine-tune tumor cell extravasation by impairing the remodeling properties of the endothelium. Importantly, we also observe endothelial remodeling at arrest sites of CTCs in mouse brain capillaries. Finally, we observed that human supratentorial brain metastases preferably develop in areas with low perfusion. These results demonstrate that hemodynamic profiles at metastatic sites regulate key steps of extravasation preceding metastatic outgrowth.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Adesão Celular , Hemodinâmica , Neoplasias Pulmonares/patologia , Melanoma/patologia , Células Neoplásicas Circulantes/patologia , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/metabolismo , Ciclo Celular , Circulação Cerebrovascular , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Neoplásicas Circulantes/metabolismo , Estudos Retrospectivos , Células Tumorais Cultivadas , Peixe-Zebra
9.
J Clin Invest ; 127(11): 4090-4103, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28972538

RESUMO

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.


Assuntos
Doenças da Medula Óssea/genética , Insuficiência Pancreática Exócrina/genética , Lipomatose/genética , Neutropenia/congênito , Partícula de Reconhecimento de Sinal/genética , Animais , Criança , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Modelos Moleculares , Neutropenia/genética , Pâncreas Exócrino/metabolismo , Fenótipo , Domínios Proteicos , Partícula de Reconhecimento de Sinal/química , Peixe-Zebra
10.
J Autoimmun ; 82: 74-84, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28545737

RESUMO

Synovial fibroblasts are key cells orchestrating the inflammatory response in arthritis. Here we demonstrate that loss of miR-146a, a key epigenetic regulator of the innate immune response, leads to increased joint destruction in a TNF-driven model of arthritis by specifically regulating the behavior of synovial fibroblasts. Absence of miR-146a in synovial fibroblasts display a highly deregulated gene expression pattern and enhanced proliferation in vitro and in vivo. Deficiency of miR-146a induces deregulation of tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) in synovial fibroblasts, leading to increased proliferation. In addition, loss of miR-146a shifts the metabolic state of fibroblasts towards glycolysis and augments the ability of synovial fibroblasts to support the generation of osteoclasts by controlling the balance of osteoclastogenic regulatory factors receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG). Bone marrow transplantation experiments confirmed the importance of miR-146a in the radioresistant mesenchymal compartment for the control of arthritis severity, in particular for inflammatory joint destruction. This study therefore identifies microRNA-146a as an important local epigenetic regulator of the inflammatory response in arthritis. It is a central element of an anti-inflammatory feedback loop in resident synovial fibroblasts, who are orchestrating the inflammatory response in chronic arthritis. MiR-146a restricts their activation, thereby preventing excessive tissue damage during arthritis.


Assuntos
Artrite/genética , Artrite/metabolismo , Fibroblastos/metabolismo , Articulações/metabolismo , Articulações/patologia , MicroRNAs/genética , Animais , Artrite/patologia , Artrite Experimental , Reabsorção Óssea/genética , Proliferação de Células , Modelos Animais de Doenças , Fibroblastos/patologia , Expressão Gênica , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Interferência de RNA , Membrana Sinovial/citologia , Membrana Sinovial/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
Front Immunol ; 8: 368, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28396673

RESUMO

Natural killer group 2, member D (NKG2D) is an invariant activatory receptor present on subsets of natural killer and T lymphocytes. It stimulates the cytolytic effector response upon engagement of its various stress-induced ligands NKG2D ligands (NKG2DL). Malignant transformation and conditioning treatment prior to hematopoietic cell transplantation (HCT) are stress factors leading to the activation of the NKG2D/NKG2DL signaling in clinical settings. In the context of HCT, NKG2D-bearing cells can kill both tumor and healthy cells expressing NKG2DL. The NKG2D/NKG2DL engagement has therefore a key role in the regulation of one of the most salient issues in allogeneic HCT, i.e., maintaining a balance between graft-vs.-leukemia effect and graft-vs.-host disease. The present review summarizes the current state of our knowledge pertaining to the role of the NKG2D and NKG2DL in HCT.

12.
Hum Mol Genet ; 26(13): 2565-2576, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28379387

RESUMO

The association of primary Sjögren's syndrome (pSS) with Major Histocompatibility Complex (MHC) alleles is quintessential of MHC-disease associations. Indeed, although disease associations with classical HLA class I and II alleles/haplotypes are amply documented, further dissection is often prevented by the strong linkage disequilibrium across the entire MHC complex. Here we study the association of pSS, not with HLA genes, but with the non-conventional MHC encoded class I gene, MICA (MHC class I chain-related gene A). MICA is selectively expressed within epithelia, and is the major ligand for the activatory receptor, NKG2D, both attributes relevant to pSS' etiology. MICA-pSS association was studied in two independent (French and UK) cohorts representing a total of 959 cases and 1,043 controls. MICA*008 allele was shown to be significantly associated with pSS (pcor=2.61 × 10-35). A multivariate logistic regression showed that this association was independent of all major known MHC-linked risk loci/alleles, as well as other relevant candidate loci that are in linkage disequilibrium with MICA*008 i.e. HLA-B*08:01, rs3131619 (T), MICB*008, TNF308A, HLA-DRB1*03:01 and HLA-DRB1*15:01 (P = 1.84 × 10-04). Furthermore, independently of the MICA*008 allele, higher levels of soluble MICA proteins were detected in sera of pSS patients compared to healthy controls. This study hence defines MICA as a new, MHC-linked, yet HLA-independent, pSS risk locus and opens a new front in our understanding of the still enigmatic pathophysiology of this disease. The fact that the soluble MICA protein is further amplified in MICA*008 carrying individuals, might also be relevant in other auto-immune diseases and cancer.


Assuntos
Antígenos de Histocompatibilidade Classe I/genética , Síndrome de Sjogren/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Antígenos HLA-B/genética , Cadeias HLA-DRB1/genética , Haplótipos , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Desequilíbrio de Ligação , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
13.
Hum Immunol ; 77(11): 1005-1007, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27881245

RESUMO

TRANSPLANTEX, a French "investment for the future" initiated consortium of leading transplant units and research laboratories across France and a number of European countries aims to unravel, through mainly high-throughput genomics (and other omics) analyses of donor and recipients, novel (a) non-HLA, histocompatibility antigens, whether inside, or outside the MHC; (b) pre/post transplantation biomarkers. This shall lead to our better understanding of the pathophysiology of (and eventually designing better therapeutics for) the graft-versus-host disease in hematopoietic cell transplants and that of chronic graft rejection after kidney transplant. Industrial developments as well as innovative teaching initiatives are also integral part of this program. The present issue of Human Immunology aims to present a first snapshot of some of the research performed by TRANPLANTEX partners.


Assuntos
Rejeição de Enxerto/prevenção & controle , Doença Enxerto-Hospedeiro/terapia , Teste de Histocompatibilidade , Imunossupressão , Transplante de Rim , Biomarcadores/metabolismo , Consenso , França , Rejeição de Enxerto/diagnóstico , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Sistema de Registros
14.
Blood ; 128(15): 1979-1986, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27549307

RESUMO

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.


Assuntos
Doença Enxerto-Hospedeiro , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe I/genética , Teste de Histocompatibilidade , Desequilíbrio de Ligação , Doença Aguda , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Estudos Retrospectivos
15.
Eur J Hum Genet ; 24(12): 1746-1751, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27381093

RESUMO

Spondylocarpotarsal synostosis syndrome (SCT) is a rare Mendelian disorder (OMIM #272460) characterized by prenatal vertebral fusion, scoliosis, short stature and carpal and tarsal synostosis. SCT is typically known as an autosomal recessive disease caused by variants in the FLNB gene. The genetic basis of the rarer cases of vertical transmissions remains unknown. In two independent families with symptoms related to autosomal dominant SCT, we identified - by exome sequencing - two protein-altering variants in the embryonic myosin heavy chain 3 (MYH3) gene. As MYH3 variants are also associated with distal arthrogryposis (DA1, DA2A, DA2B) and autosomal dominant multiple pterygium syndromes (MPS), the present study expands the phenotypic spectrum of MYH3 variants to autosomal dominant SCT. Vertebral, carpal and tarsal fusions observed in both families further confirm that MYH3 plays a key role in skeletal development.


Assuntos
Anormalidades Múltiplas/genética , Proteínas do Citoesqueleto/genética , Vértebras Lombares/anormalidades , Doenças Musculoesqueléticas/genética , Mutação , Fenótipo , Escoliose/congênito , Sinostose/genética , Vértebras Torácicas/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Exoma , Feminino , Humanos , Vértebras Lombares/patologia , Masculino , Doenças Musculoesqueléticas/patologia , Linhagem , Escoliose/genética , Escoliose/patologia , Sinostose/patologia , Vértebras Torácicas/patologia
16.
Hum Immunol ; 77(11): 1016-1023, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27060029

RESUMO

The human Major Histocompatibility Complex, known as the "Human Leukocyte Antigen (HLA)", could be defined as a "super locus" (historically called "supergene") governing the adaptive immune system in vertebrates. It also harbors genes involved in innate immunity. HLA is the most gene-dense, polymorphic and disease-associated region of the human genome. It is of critical medical relevance given its involvement in the fate of the transplanted organs/tissues and its association with more than 100 diseases. However, despite these important roles, comprehensive sequence analysis of the 4 megabase HLA locus has been limited due to technological challenges. Thanks to recent improvements in Next-Generation Sequencing (NGS) technologies however, one is now able to handle the peculiarities of the MHC notably the tight linkage disequilibrium between genes as well as their high degree of polymorphism (and hence heterozygosity). Increased read lengths, throughput, accuracy, as well as development of new bioinformatics tools now enable to efficiently generate complete and accurate full-length HLA haplotypes without phase ambiguities. The present report reviews current NGS approaches to capture, sequence and analyze HLA genes and loci. The impact of these new methodologies on various applications including HLA typing, population genetics and disease association studies are discussed.


Assuntos
Loci Gênicos/genética , Antígenos HLA/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Teste de Histocompatibilidade , Genética Populacional , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Polimorfismo Genético
17.
RMD Open ; 2(1): e000196, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26977311

RESUMO

OBJECTIVE: Mevalonate kinase (MVK) deficiency is a rare autosomal recessive auto-inflammatory disorder characterised by recurring episodes of fever associated with multiple non-specific inflammatory symptoms and caused by mutations in the MVK gene. The phenotypic spectrum is wide and depends mostly on the nature of the mutations. Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a relatively mild presentation and predominantly associated with a c.1129G>A (p.V377I) mutation in the MVK gene. We report cases of two sisters homozygous for this mutation but exhibiting distinct (symptomatic vs asymptomatic) phenotypes. METHODS: Patient history was obtained; physical and clinical examination and laboratory tests were performed; lipopolysaccharide (LPS) response of peripheral blood mononuclear cells was quantified. RESULTS: Low MVK enzymatic activity is not necessarily associated with inflammatory symptoms. Increased inflammatory cytokine secretion in response to LPS is associated with symptomatic MVK deficiency. CONCLUSIONS: Individuals who are homozygous for the common p.V377I mutation in the MVK gene may not display the characteristic inflammatory episodes diagnostic of MKD and thus may be lost for correct and timely diagnosis.

18.
Ann Rheum Dis ; 75(4): 780-3, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26338037

RESUMO

BACKGROUND AND OBJECTIVE: A germline and coding polymorphism (rs2230926) of TNFAIP3 (A20), a central gatekeeper of nuclear factor-kappa B (NF-kB) activation, was recently found associated with primary Sjögren's syndrome (pSS)-associated lymphoma in a French cohort. We aimed to replicate this association. PATIENTS AND METHODS: The rs2230926 polymorphism was genotyped in cases and controls of European ancestry from two independent cohorts from UK and France. Case control association tests were performed (Fisher's test) in the two cohorts, followed by a meta-analysis of the two cohorts. RESULTS: The UK cohort included 308 controls and 590 patients with pSS including 31 with a history of lymphoma. The French cohort consisted of 448 controls and 589 patients with pSS including 47 with lymphoma. In both cohorts, the rs2230926 missense polymorphism was not associated with pSS. However, in the UK cohort, the rs2230926G variant was significantly associated with pSS-associated lymphoma (OR=2.74, 95% CI (1.07 to 7.03), p=0.0423, compared with patients with pSS without lymphoma, and OR=3.12, 95% CI (1.16 to 8.41), p=0.0314, compared with healthy controls) as observed in the French cohort. The meta-analysis of the two cohorts confirmed these results (OR=2.48, 95% CI (1.87 to 3.28) p=0.0037 and OR=2.60, 95% CI (1.91 to 3.53) p=0.0031, respectively). CONCLUSIONS: This study confirms the role of A20 impairment in pSS-associated lymphoma. Subtle germline abnormalities of genes leading to impaired control of NF-kB activation in B cells continuously stimulated by autoimmunity enhance the risk of lymphoma.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfoma/genética , Proteínas Nucleares/genética , Síndrome de Sjogren/genética , Estudos de Casos e Controles , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , França , Doença de Hodgkin/genética , Humanos , Modelos Logísticos , Linfoma/complicações , Linfoma de Células B/genética , Análise Multivariada , Micose Fungoide/genética , Polimorfismo de Nucleotídeo Único , Síndrome de Sjogren/complicações , Neoplasias Cutâneas/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Reino Unido
19.
Immunol Rev ; 267(1): 88-116, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26284473

RESUMO

Human and mouse NKG2D ligands (NKG2DLs) are absent or only poorly expressed by most normal cells but are upregulated by cell stress, hence, alerting the immune system in case of malignancy or infection. Although these ligands are numerous and highly variable (at genetic, genomic, structural, and biochemical levels), they all belong to the major histocompatibility complex class I gene superfamily and bind to a single, invariant, receptor: NKG2D. NKG2D (CD314) is an activating receptor expressed on NK cells and subsets of T cells that have a key role in the recognition and lysis of infected and tumor cells. Here, we review the molecular diversity of NKG2DLs, discuss the increasing appreciation of their roles in a variety of medical conditions, and propose several explanations for the evolutionary force(s) that seem to drive the multiplicity and diversity of NKG2DLs while maintaining their interaction with a single invariant receptor.


Assuntos
Variação Genética/imunologia , Genômica , Antígenos de Histocompatibilidade Classe I/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Animais , Variação Genética/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Ligantes , Camundongos , Modelos Genéticos , Modelos Imunológicos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética
20.
Immunogenetics ; 67(5-6): 289-93, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25940109

RESUMO

Despite that the association of Behçet's disease (BD) with the HLA-B5 was first established in the 1970s, a number of recent genome-wide association studies have both confirmed and furthered this association--in various populations--to individual SNPs both inside and outside the HLA. The former include HLA-B, MICA, and HLA-A, while the latter encompass IL10 and IL23R-IL12RB2 regions. The present study examined whether some of these SNPs could be replicated in an Iranian population, where the prevalence of disease is amply documented. Eight SNPs were selected and tested in 552 patients and 417 controls. These were rs7539328, rs12119179, rs1495965, rs1518111, and rs1800871 in IL10 and IL23R-IL12RB2 regions and rs114854070, rs12525170, and rs76546355 (formerly rs116799036) in the HLA locus. The well-known BD-associated genes HLA-B and MICA were independently genotyped. Although we were not able to formally replicate the association with IL10 and IL23R-IL12RB2, we do report that BD in Iran is strongly associated with HLA-B*51, MICA-A6, and the three HLA-linked SNPs (odds ratio (OR) = 3.38, P = 6.21 × 10(-14); OR = 2.08, P = 1.58 × 10(-13); and OR = 1.67-4.05, P = 1.45 × 10(-04) to 4.79 × 10(-34), respectively). Our data further indicate that the robust HLA-B/MICA association may be explained by a single variant (rs76546355) between the two genes. Overall, these data contribute to a better appraisal of the intriguing linkage between BD and the ancient Silk Route, spanning from the Mediterranean shores to Japan.


Assuntos
Síndrome de Behçet/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos de Histocompatibilidade Classe I/genética , Feminino , Estudos de Associação Genética , Humanos , Interleucina-10/genética , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Receptores de Interleucina-12/genética
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