RESUMO
Rothmund-Thomson syndrome (OMIM #268400) is a severe autosomal recessive genodermatosis: characterised by growth retardation, hyperpigmentation and frequently accompanied by congenital bone defects, brittle hair and hypogonadism. Mutations in helicase RECQ4 gene are responsible for a subset of cases of RTS. Only six mutations have been reported, thus, far and each affecting the coding sequence or the splice junctions. We report the first homozygous mutation in RECQ4 helicase: 2746-2756-delTGGGCTGAGGC in IVS8 responsible for the severe phenotype associated with RTS in a Malaysian pedigree. We report also a 5321 G-->A transition in exon 17 and the updated list of the RECQ4 gene mutations.
Assuntos
DNA Helicases/genética , Mutação , Síndrome de Rothmund-Thomson/genética , Adolescente , Processamento Alternativo , Amputação Cirúrgica , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/etiologia , Neoplasias Ósseas/cirurgia , Doenças em Gêmeos , Éxons , Feminino , Homozigoto , Humanos , Masculino , Osteossarcoma/tratamento farmacológico , Osteossarcoma/etiologia , Osteossarcoma/cirurgia , Linhagem , RecQ Helicases , Síndrome de Rothmund-Thomson/complicações , Síndrome de Rothmund-Thomson/terapia , Gêmeos DizigóticosRESUMO
Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
Assuntos
Artrite Reumatoide/genética , Mapeamento Cromossômico/métodos , Loci Gênicos , Predisposição Genética para Doença , Autoanticorpos/sangue , Autoanticorpos/genética , Mapeamento Cromossômico/instrumentação , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , População Branca/genéticaAssuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/epidemiologia , Testes Genéticos/métodos , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/metabolismo , Proteínas Serina-Treonina Quinases/genética , Radioterapia/estatística & dados numéricos , Proteínas Supressoras de Tumor/genética , Proteínas Mutadas de Ataxia Telangiectasia , Biomarcadores Tumorais/genética , Carga Corporal (Radioterapia) , Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Estudos de Casos e Controles , Análise Mutacional de DNA/métodos , Incidência , Neoplasias Induzidas por Radiação/genética , Polimorfismo Genético , Doses de Radiação , Medição de Risco/métodos , Fatores de Risco , Estados Unidos/epidemiologia , Saúde da MulherRESUMO
OBJECTIVE: The Type 1 Diabetes Genetics Consortium has collected type 1 diabetic families worldwide for genetic analysis. The major genetic determinants of type 1 diabetes are alleles at the HLA-DRB1 and DQB1 loci, with both susceptible and protective DR-DQ haplotypes present in all human populations. The aim of this study is to estimate the risk conferred by specific DR-DQ haplotypes and genotypes. RESEARCH DESIGN AND METHODS: Six hundred and seven Caucasian families and 38 Asian families were typed at high resolution for the DRB1, DQA1, and DQB1 loci. The association analysis was performed by comparing the frequency of DR-DQ haplotypes among the chromosomes transmitted to an affected child with the frequency of chromosomes not transmitted to any affected child. RESULTS: A number of susceptible, neutral, and protective DR-DQ haplotypes have been identified, and a statistically significant hierarchy of type 1 diabetes risk has been established. The most susceptible haplotypes are the DRB1*0301-DQA1*0501-DQB1*0201 (odds ratio [OR] 3.64) and the DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB*0302, and DRB1*0402-DQA1*0301-DQB1*0302 haplotypes (ORs 11.37, 8.39, and 3.63), followed by the DRB1*0404-DQA1*0301-DQB1*0302 (OR 1.59) and the DRB1*0801-DQB1*0401-DQB1*0402 (OR 1.25) haplotypes. The most protective haplotypes are DRB1*1501-DQA1*0102-DQB1*0602 (OR 0.03), DRB1*1401-DQA1*0101-DQB1*0503 (OR 0.02), and DRB1*0701-DQA1*0201-DQB1*0303 (OR 0.02). CONCLUSIONS: Specific combinations of alleles at the DRB1, DQA1, and DQB1 loci determine the extent of haplotypic risk. The comparison of closely related DR-DQ haplotype pairs with different type 1 diabetes risks allowed identification of specific amino acid positions critical in determining disease susceptibility. These data also indicate that the risk associated with specific HLA haplotypes can be influenced by the genotype context and that the trans-complementing heterodimer encoded by DQA1*0501 and DQB1*0302 confers very high risk.
Assuntos
Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Idade de Início , Povo Asiático/genética , Criança , Pré-Escolar , Família , Feminino , Predisposição Genética para Doença , Genótipo , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Cadeias HLA-DRB1 , Humanos , Masculino , Fatores de Risco , População Branca/genéticaRESUMO
The phosphatidyl inositol 3-kinase-like kinases (PIKKs), ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) regulate parallel damage response signalling pathways. ATM is reported to be activated by DNA double-strand breaks (DSBs), whereas ATR is recruited to single-stranded regions of DNA. Although the two pathways were considered to function independently, recent studies have demonstrated that ATM functions upstream of ATR following exposure to ionising radiation (IR) in S/G2. Here, we show that ATM phosphorylation at Ser1981, a characterised autophosphorylation site, is ATR-dependent and ATM-independent following replication fork stalling or UV treatment. In contrast to IR-induced ATM-S1981 phosphorylation, UV-induced ATM-S1981 phosphorylation does not require the Nbs1 C-terminus or Mre11. ATR-dependent phosphorylation of ATM activates ATM phosphorylation of Chk2, which has an overlapping function with Chk1 in regulating G2/M checkpoint arrest. Our findings provide insight into the interplay between the PIKK damage response pathways.