RESUMO
Intellectual disability (ID), often attributed to autosomal-recessive mutations, occurs in 40% of autism spectrum disorders (ASDs). For this reason, we conducted a genome-wide analysis of runs of homozygosity (ROH) in simplex ASD-affected families consisting of a proband diagnosed with ASD and at least one unaffected sibling. In these families, probands with an IQ ≤ 70 show more ROH than their unaffected siblings, whereas probands with an IQ > 70 do not show this excess. Although ASD is far more common in males than in females, the proportion of females increases with decreasing IQ. Our data do support an association between ROH burden and autism diagnosis in girls; however, we are not able to show that this effect is independent of low IQ. We have also discovered several autism candidate genes on the basis of finding (1) a single gene that is within an ROH interval and that is recurrent in autism or (2) a gene that is within an autism ROH block and that harbors a homozygous, rare deleterious variant upon analysis of exome-sequencing data. In summary, our data suggest a distinct genetic architecture for participants with autism and co-occurring intellectual disability and that this architecture could involve a role for recessively inherited loci for this autism subgroup.
Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Estudos de Associação Genética/métodos , Deficiência Intelectual/genética , Criança , Cromossomos Humanos/genética , Feminino , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/genética , Genética Populacional/métodos , Homozigoto , Humanos , Testes de Inteligência , Masculino , Linhagem , Fenótipo , Fatores SexuaisRESUMO
Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.
Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Mutação/genética , Translocação Genética/genética , Algoritmos , Neoplasias da Mama/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Análise Mutacional de DNA , Exoma/genética , Feminino , Fusão Gênica/genética , Humanos , Proteínas de Membrana/genética , México , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , VietnãRESUMO
The antineoplastic prodrug Cloretazine exerts its cytotoxicity via a synergism between 2-chloroethylating and carbamoylating activities that are cogenerated upon activation in situ. Cloretazine is reported here to inhibit the nucleotidyl-transferase activity of purified human DNA polymerase beta (Pol beta), a principal enzyme of DNA base excision repair (BER). The 2-chloroethylating activity of Cloretazine alkylates DNA at the O(6) position of guanine bases resulting in 2-chloroethoxyguanine monoadducts, which further react to form cytotoxic interstrand DNA crosslinks. Alkylated DNA is often repaired via BER in vivo. Inhibition of the polymerase activity of Pol beta may account for some of the synergism between Cloretazine's two reactive subspecies in cytotoxicity assays. This inhibition was only observed using agents with carbamoylating activity. Furthermore, while therapeutically relevant concentrations of Cloretazine inhibited the polymerase activity of Pol beta, the enzyme's lyase activity, which may also participate in BER, was not significantly inhibited.
