RESUMO
MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17â¼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17â¼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17â¼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17â¼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.
Assuntos
Deleção de Genes , Mutação em Linhagem Germinativa , MicroRNAs/genética , Família Multigênica , Desenvolvimento Musculoesquelético/genética , Animais , Cromossomos Humanos Par 13/genética , Bases de Dados Genéticas , Obstrução Duodenal/genética , Embrião de Mamíferos , Atresia Esofágica/genética , Pálpebras/anormalidades , Feminino , Haploinsuficiência , Humanos , Deficiência Intelectual , Deformidades Congênitas dos Membros/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/metabolismo , Microcefalia/genética , Modelos Animais , Linhagem , Reação em Cadeia da Polimerase , Fístula TraqueoesofágicaRESUMO
The increased prevalence of schizophrenia among patients with the 22q11 interstitial deletion associated with DiGeorge syndrome has suggested the existence of a susceptibility gene for schizophrenia within the DiGeorge syndrome chromosomal region (DGCR) on 22q11. Screening for genomic rearrangements of 23 genes within or at the boundaries of the DGCR in 63 unrelated schizophrenic patients and 68 unaffected controls, using quantitative multiplex PCR of short fluorescent fragments (QMPSF), led us to identify, in a family including two schizophrenic subjects, a heterozygous deletion of the entire PRODH gene encoding proline dehydrogenase. This deletion was associated with hyperprolinemia in the schizophrenic patients. In addition, two heterozygous PRODH missense mutations (L441P and L289M), detected in 3 of 63 schizophrenic patients but in none among 68 controls, were also associated with increased plasma proline levels. Segregation analysis within the two families harboring respectively the PRODH deletion and the L441P mutation showed that the presence of a second PRODH nucleotide variation resulted in higher levels of prolinemia. In two unrelated patients suffering from severe type I hyperprolinemia with neurological manifestations, we identified a homozygous L441P PRODH mutation, associated with a heterozygous R453C substitution in one patient. These observations demonstrate that type I hyperprolinemia is present in a subset of schizophrenic patients, and suggest that the genetic determinism of type I hyperprolinemia is complex, the severity of hyperprolinemia depending on the nature and number of hits affecting the PRODH locus.