RESUMO
Haploinsufficiency of the human 5q35 region spanning the NSD1 gene results in a rare genomic disorder known as Sotos syndrome (Sotos), with patients displaying a variety of clinical features, including pre- and postnatal overgrowth, intellectual disability, and urinary/renal abnormalities. We used chromosome engineering to generate a segmental monosomy, i.e., mice carrying a heterozygous 1.5-Mb deletion of 36 genes on mouse chromosome 13 (4732471D19Rik-B4galt7), syntenic with 5q35.2-q35.3 in humans (Df(13)Ms2Dja ( +/- ) mice). Surprisingly Df(13)Ms2Dja ( +/- ) mice were significantly smaller for their gestational age and also showed decreased postnatal growth, in contrast to Sotos patients. Df(13)Ms2Dja ( +/- ) mice did, however, display deficits in long-term memory retention and dilation of the pelvicalyceal system, which in part may model the learning difficulties and renal abnormalities observed in Sotos patients. Thus, haploinsufficiency of genes within the mouse 4732471D19Rik-B4galt7 deletion interval play important roles in growth, memory retention, and the development of the renal pelvicalyceal system.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Modelos Animais de Doenças , Crescimento e Desenvolvimento/genética , Transtornos da Memória/genética , Síndrome de Sotos/genética , Absorciometria de Fóton , Animais , Southern Blotting , Pesos e Medidas Corporais , Hibridização Genômica Comparativa , Primers do DNA/genética , Marcação de Genes/métodos , Haploinsuficiência/genética , Técnicas Histológicas , Humanos , Hibridização in Situ Fluorescente , Rim/anormalidades , Camundongos , Síndrome de Sotos/patologiaRESUMO
Haploinsufficiency of part of human chromosome 21 results in a rare condition known as Monosomy 21. This disease displays a variety of clinical phenotypes, including intellectual disability, craniofacial dysmorphology, skeletal and cardiac abnormalities, and respiratory complications. To search for dosage-sensitive genes involved in this disorder, we used chromosome engineering to generate a mouse model carrying a deletion of the Lipi-Usp25 interval, syntenic with 21q11.2-q21.1 in humans. Haploinsufficiency for the 6 genes in this interval resulted in no gross morphological defects and behavioral analysis performed using an open field test, a test of anxiety, and tests for social interaction were normal in monosomic mice. Monosomic mice did, however, display impaired memory retention compared to control animals. Moreover, when fed a high-fat diet (HFD) monosomic mice exhibited a significant increase in fat mass/fat percentage estimate compared with controls, severe fatty changes in their livers, and thickened subcutaneous fat. Thus, genes within the Lipi-Usp25 interval may participate in memory retention and in the regulation of fat deposition.
Assuntos
Deleção Cromossômica , Dieta Hiperlipídica , Haploinsuficiência/fisiologia , Absorciometria de Fóton , Animais , Comportamento Animal , Southern Blotting , Linhagem Celular , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/metabolismo , Feminino , Haploinsuficiência/genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Aprendizagem em Labirinto , Camundongos , Monossomia/genética , Reconhecimento Psicológico , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder of childhood, affecting approximately 5-10% of children. ADHD is considered to be a multifactorial disorder because both genetic and environmental components may contribute to its progress. The etiology of attention deficit hyperactivity disorder (ADHD) is unknown, however family, twin and adoption studies have suggested that genetic factors are very important in its etiopathogenesis. The research of genetic basis of ADHD consists of linkage analysis, candidate gene approach and association studies. These analyses and also investigations on animal models of disease suggest that mutations in genes involved in dopaminergic, serotonergic and adrenergic systems are likely to be responsible for ADHD.