RESUMO
Haploinsufficiency of the NSD1 gene due to 5q35 microdeletions or intragenic mutations causes Sotos syndrome (SoS). In 46 of the 49 Japanese deletion cases, common deletion breakpoints were located at two flanking low copy repeats (LCRs), implying that non-allelic homologous recombination (NAHR) between LCRs is the major mechanism for the common deletion. In the other three cases of atypical deletions, the mechanism(s) of deletions remains unanswered. We characterized the atypical microdeletions using fluorescence in situ hybridization (FISH), quantitative real-time polymerase chain reaction (qPCR), and Southern blot hybridization. All the deletion breakpoints in the three cases were successfully determined at the nucleotide level. Two deletions are 1.07 Mb (SoS19) and 1.23 Mb (SoS109) in size, and another consisted of two deletions with sizes of 28 kb and 0.72 Mb, intervened by an intact 29-kb segment (SoS44). All deletions were smaller than a typical 1.9-Mb common deletion. Alu elements were identified in both deletion breakpoints in SoS19, one of deletion breakpoints in SoS109, and both deletion breakpoints of the proximal 28-kb deletion in SoS44. Alu-mediated NAHR is strongly suggested at least in two of atypical deletions. Finally, qPCR is a very useful method to determine deletion breakpoints even in repeat-related regions.
Assuntos
Anormalidades Múltiplas/genética , Elementos Alu/genética , Cromossomos Humanos Par 5/genética , Anormalidades Craniofaciais/genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Deleção de Sequência/genética , Sequência de Bases , Quebras de DNA de Cadeia Dupla , Humanos , Hibridização in Situ Fluorescente , Modelos Genéticos , Dados de Sequência Molecular , Recombinação Genética , SíndromeRESUMO
NR-binding SET-domain-containing protein (NSD1) is a mouse nuclear protein containing su(var)3-9, enhancer-of-zeste, trithorax (SET), proline-tryptophan-tryptophan-proline (PWWP) and plant homeodomain protein (PHD)-finger domains (Huang et al., EMBO J. 17 (1998) 3398). This protein also has two other distinct nuclear receptor (NR)-interaction domains, called NID(-L) and NID(+L), and acts as both a NR corepressor and a coactivator by interacting directly with the ligand-binding domain of several NRs. Thus, NSD1 is a bifunctional, transcriptional, intermediary factor. We isolated the human homologue (NSD1) of the mouse NSD1 gene (Nsd1), mapped it to human chromosome 5q35, and characterized its genomic structure. NSD1 consists of at least 23 exons. Its cDNA is 8552 bp long, has an 8088 bp open reading frame, contains at least six functional domains (SET, PWWP-I, PWWP-II, PHD-I, PHD-II, and PHD-III) and ten putative nuclear localization signals, and encodes 2696 amino acids. NSD1 shows 86% identity with the mouse Nsd1 at the nucleotide level, and 83% at the amino acid level. NSD1 is expressed in the fetal/adult brain, kidney, skeletal muscle, spleen, and the thymus, and faintly in the lung. Two different transcripts (9.0 and 10.0 kb) were consistently observed in various fetal and adult tissues examined. These findings favor the character of NSD1 as a nucleus-localized, basic transcriptional factor and also a bifunctional transcriptional regulator, such as that of the mouse Nsd1. It remains to be investigated whether mutations of NSD1 lead to a specific phenotype in man.
Assuntos
Proteínas de Transporte/genética , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Nucleares/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação , Northern Blotting , Mapeamento Cromossômico , Cromossomos Humanos Par 5/genética , Clonagem Molecular , DNA Complementar/química , DNA Complementar/genética , DNA Complementar/isolamento & purificação , Éxons , Feto , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Genes/genética , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , Íntrons , Camundongos , Dados de Sequência Molecular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Alinhamento de Sequência , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Distribuição TecidualAssuntos
Pareamento de Bases/genética , Proteínas de Transporte/genética , Deficiências do Desenvolvimento/genética , Gigantismo/genética , Deficiência Intelectual/genética , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Nucleares/genética , Deleção de Sequência/genética , Adulto , Pai , Genes Dominantes/genética , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Masculino , Núcleo Familiar , SíndromeAssuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Peptídeos e Proteínas de Sinalização Intracelular , Mutação , Proteínas Nucleares/genética , Processamento Alternativo/genética , Análise Mutacional de DNA , Feminino , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Masculino , Dados de Sequência Molecular , Núcleo Familiar , Valor Preditivo dos TestesAssuntos
Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Transtornos do Crescimento/patologia , Deficiência Intelectual/patologia , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Nucleares/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , DNA/química , DNA/genética , Análise Mutacional de DNA , Feminino , Deleção de Genes , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Masculino , Mutação , SíndromeRESUMO
Sotos syndrome is an overgrowth disorder that manifests characteristic dysmorphic features, neurological problems, and an increased risk for cancers and heart defects. Alterations of NSD1 are responsible for this disease. A subset of cases arise from deletions, which is of interest as the factor XII locus lies in close proximity to NSD1. This case report describes an individual with Sotos syndrome and factor XII deficiency, providing a potential link between these two genes and, consequently, expanding the clinical phenotype of Sotos syndrome.