RESUMO
Fragile X syndrome is one of 14 trinucleotide repeat diseases. It arises due to expansion of a CGG repeat which is present in the 5'-untranslated region of the FMR1 gene, disruption of which leads to mental retardation. The mechanisms involved in trinucleotide repeat expansion are poorly understood and to date, transgenic mouse models containing transgenic expanded CGG repeats have failed to reproduce the instability seen in humans. As both cis-acting factors and the genomic context of the CGG repeat are thought to play a role in expansion, we have now generated a knock-in mouse Fmr1 gene in which the murine (CGG)8 repeat has been exchanged with a human (CGG)98 repeat. Unlike other CGG transgenic models, this model shows moderate CGG repeat instability upon both in maternal and paternal transmission. This model will now enable us to study the timing and the mechanism of repeat expansion in mice.
Assuntos
Síndrome do Cromossomo X Frágil/genética , Proteínas do Tecido Nervoso/genética , Regiões Promotoras Genéticas , Proteínas de Ligação a RNA , Repetições de Trinucleotídeos , Alelos , Animais , Modelos Animais de Doenças , Eletroporação , Feminino , Proteína do X Frágil da Deficiência Intelectual , Amplificação de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Polimorfismo Genético , Células-TroncoRESUMO
Fragile X syndrome is caused by an expansion of the CGG repeat present in the 5' UTR of the FMR1 gene. A lot has been elucidated about the genetics of the disease, but not much is known about the mechanisms involved in repeat instability. Transgenic animals with a premutation allele [(CGG)11AGG(CGG)60CAG(CGG)8] in the human FMR1 promoter were generated to study the inheritance of this repeat in mice. Three independent lines, B6, B7 and B29, in total 263 transgenic animals, were tested for repeat instability. In all meiosis and mitosis tested, the repeat inherited stably. This suggests that other factors might be important in repeat (in)stability.
Assuntos
Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA , Repetições de Trinucleotídeos/genética , Alelos , Animais , Sequência de Bases , DNA Recombinante , Feminino , Proteína do X Frágil da Deficiência Intelectual , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genéticaRESUMO
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with unknown pathophysiology that is characterised by arteriovenous lesions and recurrent haemorrhage in virtually every organ. Linkage of HHT to markers on chromosome 9q has recently been reported. In this study we report confirmation of this localisation in three unrelated families of Dutch origin. A fourth unrelated HHT family, in which considerably fewer pulmonary arteriovenous malformations (PAVM) were present, yielded evidence for non-linkage to this region. We conclude that HHT is a genetically heterogeneous disorder and our results indicate that the presence of PAVM may be more common in patients with a chromosome 9 linked form of HHT than in patients with the non-linked form.