100 research outputs found
Cernunnos, a novel V(D)J recombination /non homologus end-joining factor, is mutated in human T and B cell immunodeficiency associated with microcephaly.
No full textDNA double-strand breaks (DSBs) occur at random upon genotoxic stresses and represent obbligatory intermediates during physiological DNA rearrangement events such as the V(D)J recombination in the immune system. DSBs, which are among the most toxic DNA lesions, are preferentially repaired by the nonhomologous end-joining (NHEJ) pathway in higher eukaryotes. Failure to properly repair DSBs results in genetic instability, developmental delay, and various forms of immunodeficiency. Here we describe five patients with growth retardation, microcephaly, and immunodeficiency characterized by a profound T + B lymphocytopenia. An increased cellular sensitivity to ionizing radiation, a defective V(D)J recombination, and an impaired DNA-end ligation process both in vivo and in vitro are indicative of a general DNA repair defect in these patients. All five patients carry mutations in the Cernunnos gene, which was identified through cDNA functional complementation cloning. Cernunnos/XLF represents a novel DNA repair factor essential for the NHEJ pathway
Devenir rénal à long terme chez des patients ayant eu un diagnostic anténatal d'uropathie obstructive basse (corrélation avec les paramètres biochimiques urinaires prénataux)
No full textLes uropathies obstructives sont principalement découvertes en période anténatale sur les échographies. Elles sont les principales causes d insuffisance rénale chronique (IRC) chez l enfant. Leur retentissement sur la fonction rénale est très variable, de nul à l insuffisance rénale terminale parfois très précoce. La biochimie fœtale à pour but d aider à évaluer le pronostic rénal dans ces cas. Des marqueurs urinaires fœtaux (ß2 microglobuline, sodium, calcium urinaires) ont montré une bonne corrélation avec le devenir rénal à 2 ans. Nous avons étudiés rétrospectivement ces marqueurs chez des patients présentant des valves de l urètre postérieur ou un reflux vésico-urétéral de haut grade (deux diagnostics fréquents) avec un recul de près de 10 ans. Nous avons confirmé une bonne corrélation entre un taux bas de ß2 microglobuline (inférieur à 1,66mg/L) et une bonne fonction rénale à long terme (débit de filtration glomérulaire ou DFG > 60ml/min/1,73m2) avec une bonne spécificité (90%) mais une sensibilité faible, sans pouvoir confirmer ces données pour les autres marqueurs (sodium, calcium non significatif). Pour un taux de ß2 microglobuline urinaire >3mg/L, l évolution vers l IRC avec DFG < 30mL/min/1,73m2 se fait dans la moitié des cas (sensibilité 100%, spécificité 60%, VPN 100%). Nous avons également confirmé la bonne corrélation entre nadir de créatinine ainsi que DFG à un an avec la fonction rénale à log terme. Nous n avons étonnement pas retrouvé de lien entre volume du liquide amniotique et devenir rénal à long terme. La biochimie fœtale a donc un rôle important pour aider à déterminer la fonction rénale à long terme de fœtus atteints d uropathie obstructive.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF
O Brasil e a execução de sentença da Corte Interamericana de Direitos Humanos
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Jurídicas. Programa de Pós-Graduação em DireitoEstudo sobre o Brasil e a execução de sentença da Corte Interamericana de Direitos Humanos. Enfoca o sistema normativo interamericano dos direitos humanos, ressaltando a Convenção Americana sobre Direitos Humanos (CADH), com os seus órgãos de monitoramento e jurisdicional: Comissão Interamericana de Direitos Humanos (CIDH) e Corte Interamericana de Direito Humanos (CtIADH). Examina as implicações jurídicas do reconhecimento pelo Estado brasileiro da competência obrigatória da Corte Interamericana de Direitos Humanos, nos termos do Artigo 62 da CADH. A partir desse reconhecimento a CtIADH passa a ter competência para processar e julgar o Estado por violações dos direitos humanos. Analisa quais são as possibilidades que o ordenamento jurídico brasileiro oferece para a execução de sentença de reparação da CtIADH, observando a necessidade da criação de uma lei específica para regulamentar internamente o cumprimento desta espécie de decisão
RANK-dependent autosomal recessive osteopetrosis: Characterization of five new cases with novel mutations
No full textAutosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder attributed to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast rich, but recently two subsets of osteoclast-poor ARO have been recognized as caused by defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a single-nucleotide insertion. Immunological investigation in three of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all five patients almost completely cured the disease even when carried out in late infancy. Hypercalcemia was the most important posttransplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis. (C) 2012 American Society for Bone and Mineral Researc
Transplantation of Lymphoid Cells in Patients with Severe Combined Immunodeficiency (SCID)
No full textA homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype
No full textInherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec
Genotoxic stress increases cytoplasmic mitochondrial DNA editing by human APOBEC3 mutator enzymes at a single cell level
No full textInternational audienceHuman cells are stressed by numerous mechanisms that can lead to leakage of mitochondrial DNA (mtDNA) to the cytoplasm and ultimately apoptosis. this agonist DNA constitutes a danger to the cell and is counteracted by cytoplasmic DNases and APOBEC3 cytidine deamination of DNA. To investigate APOBEC3 editing of leaked mtDNA to the cytoplasm, we performed a PCR analysis of APOBEC3 edited cytoplasmic mtDNA (cymtDNA) at the single cell level for primary CD4 + T cells and the established P2 EBV blast cell line. Up to 17% of primary CD4 + T cells showed signs of APOBEC3 edited cymtDNA with ~50% of all mtDNA sequences showing signs of APOBEC3 editing-between 1500-5000 molecules. Although the P2 cell line showed a much lower frequency of stressed cells, the number of edited mtDNA molecules in such cells was of the same order. Addition of the genotoxic molecules, etoposide or actinomycin D increased the number of cells showing APOBEC3 edited cymtDNA to around 40%. These findings reveal a very dynamic image of the mitochondrial network, which changes considerably under stress. APOBEC3 deaminases are involved in the catabolism of mitochondrial DNA to circumvent chronic immune stimulation triggered by released mitochondrial DNA from damaged cells. The APOBEC3 (A3) locus encodes a series of seven genes encoding six functional endogenous cytidine deam-inases with substrate specificity for single stranded DNA (ssDNA) 1. They leave DNA peppered with uracil residues. This process is referred to as genetic editing as it occurs post replication. A3 enzymes leave a telltale editing signature in DNA: most A3 enzymes preferentially edit a cytidine residue in the context of 5′TpC with the exception of A3G, which prefers 5′CpC dinucleotides 2-6. The antiviral role of these A3 enzymes was initially highlighted by their impact on HIV and HBV replication 6-9 and the fact that several A3 genes can be up-regulated by interferon α 10-12. A3 can restrict the transposition of SINE and LINE retroelements 13,14 and mitochondrial DNA (mtDNA) in cell lines and tissues, all of which show the A3 editing signature-5′TpC and 5′CpC are preferentially deam-inated 15. For the latter, the target was cytoplasmic mtDNA (cymtDNA) in keeping with the observation that all A3 enzymes are unable to access the mitochondrial network 15. In addition, A3A and to a lesser extent A3B, were shown to target chromosomal DNA non-specifically, leading to hypermutated DNA with up to 70% of cyti-dine residues deaminated 15,16. A3A and A3B-induced editing occur predominantly on the lagging strand during DNA replication 17,18. Interestingly, A3A and A3B can edit 5-methylcytidine (5MeC) residues in ssDNA which makes sense given that 5MeC is found exclusively in the nucleus 16,19-21. Uracil bases in DNA are excised by uracil N-glycosidase (UNG) that initiates DNA damage responses, which can result in either DNA repair or catabolism
Screening of functional and positional candidate genes in families with common variable immunodeficiency
No full textBackground: Common variable immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies with complex clinical and immunological phenotypes. The recent discovery that some CVID patients show monogenic defects in the genes encoding ICOS, TACI or CD19 prompted us to investigate several functional candidate genes in individuals with CVID.Results: The exonic, protein coding regions of the genes encoding: APRIL, BCMA, IL10, IL10R alpha, IL10R beta, IL21, IL21R, and CCL18, were analyzed primarily in familial CVID cases, who showed evidence of genetic linkage to the respective candidate gene loci and CVID families with a recessive pattern of inheritance. Two novel SNPs were identified in exon 5 and exon 8 of the IL21R gene, which segregated with the disease phenotype in one CVID family. Eleven additional SNPs in the genes encoding BCMA, APRIL, IL10, IL10Ra, IL21 and IL21R were observed at similar frequencies as in healthy donors.Conclusion: We were unable to identify obvious disease causing mutations in the protein coding regions of the analyzed genes in the studied cohort
RANK‐dependent autosomal recessive osteopetrosis: Characterization of five new cases with novel mutations
No full textAutosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder due to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast-rich, but recently 2 subsets of osteoclast-poor ARO have been recognised as due to defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterisation of 5 additional unpublished patients from 4 unrelated families in which we found 5 novel mutations in the TNFRSF11A gene, including 2 missense and 2 nonsense mutations and a single-nucleotide insertion. Immunological investigation in 3 of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all 5 patients almost completely cured the disease even when carried out in late infancy. Hypercalcaemia was the most important post-transplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis. (c) 2011 American Society for Bone and Mineral Research
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