Phenotype consequence of high repeat FMR1 alleles

高重复 FMR1 等位基因的表型后果

• 批准号: 6334086
• 负责人: Stephanie L. Sherman
• 金额: $ 7.62万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-15 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6334086
• 关键词: RNA binding protein; alleles; cognition; family genetics; female; follicle stimulating hormone; fragile X syndromes; gene expression; genetic carriers; genetic regulation; genetic screening; genetic susceptibility; human subject; male; messenger RNA; molecular genetics; neuropsychological tests; nucleic acid repetitive sequence; ovary disorder; patient oriented research; psychobiology; sex linked trait

The fragile X syndrome, a type of inherited mental retardation, is due to the silencing of the FMR1 X-linked gene. In over 98% of cases, the mutation is due to an expansion of an unstable CGG repeat sequence located in the 5' untranslated region of the gene. Once over 200 repeats, the FMR1 gene is hypermethylated and consequently no message is transcribed. Based on our previous work and that of others, we have suggested that, in addition to this "full" mutation, an increased number of CGG repeats may influence an individual's cognitive and behavioral performance. That is, long repeat tracts found among intermediate and premutation alleles (those with 41-199 repeats), although unmethylated, may perturb the transcription/translation machinery or may alter binding properties of other proteins. There is convincing evidence for an underlying molecular etiology related to long repeat tracts in the FMR1 gene, as 21% of women who carry the premutation allele at risk for premature ovarian failure. Given the FMR1 gene is known to play a role in normal brain function, examination of a cognitive and behavioral consequence of FMR1 high repeat alleles is an important next step. In our current grant, we are ascertaining carriers of high repeat alleles to determine if there is a specific neuropsychological profile associated with high repeat alleles, and among women, to further identify specific FMR1-related risk factors associated with ovarian function. In this proposal, we request funds to enhance this comprehensive project by extending the phenotype definition based on current, exciting findings. First, a preliminary study has found that pre-menopausal premutation carriers had high follicle stimulating hormone levels, suggesting that all premutation carriers may have ovarian dysfunction, not only a subset. We propose to determine the hormone profile of high repeat carriers to more accurately define the phenotype related to ovarian function. Secondly, and importantly for both the neuropsychological and ovarian function components, we propose to determine the FMR1 mRNA and FMRP protein levels of high repeat carriers to better define the affect of long CGG repeat tracts. Based on our preliminary studies and those of others, males who carry the premutation have increased levels of mRNA, but decreased levels of FMRP. This exciting finding provides the impetus to apply this newly developed technology to our current study population to increase the power to define the impact of the FMR1 gene on cognitive and behavioral performance and for women on ovarian function.

脆性X综合征是一种遗传性智力低下，是由于FMR1 X连锁基因沉默所致。在超过98%的病例中，突变是由于位于基因5‘非翻译区的一个不稳定的CGG重复序列的扩张。一旦重复超过200次，FMR1基因就会超甲基化，因此不会转录任何消息。基于我们之前的工作和其他人的工作，我们提出，除了这种“完全”突变之外，CGG重复次数的增加可能会影响个体的认知和行为表现。也就是说，在中间和前突变等位基因(具有41-199个重复序列的等位基因)中发现的长重复区域，尽管没有甲基化，但可能会扰乱转录/翻译机制或可能改变其他蛋白质的结合特性。有令人信服的证据表明，潜在的分子病因学与FMR1基因的长重复片段有关，因为21%携带前突变等位基因的女性有早衰的风险。鉴于已知FMR1基因在正常大脑功能中发挥作用，下一步重要的是检查FMR1高重复等位基因对认知和行为的影响。在我们目前的资助中，我们正在确定高重复等位基因的携带者，以确定是否存在与高重复等位基因相关的特定神经心理特征，并在女性中进一步确定与卵巢功能相关的特定FMR1相关风险因素。在这份提案中，我们申请资金，通过扩展基于当前令人兴奋的发现的表型定义来加强这一综合项目。首先，一项初步研究发现，绝经前前突变携带者的卵泡刺激素水平较高，这表明所有前突变携带者可能都有卵巢功能障碍，而不仅仅是一个亚群。我们建议确定高重复频率携带者的激素谱，以更准确地定义与卵巢功能相关的表型。其次，对于神经心理和卵巢功能成分，我们建议测定高重复序列携带者的FMR1mRNA和FMRP蛋白水平，以更好地确定长CGG重复序列的影响。根据我们和其他人的初步研究，携带前突变的男性的mRNA水平增加，但FMRP水平降低。这一令人兴奋的发现为将这项新开发的技术应用于我们目前的研究人群提供了动力，以增加确定FMR1基因对认知和行为表现以及女性对卵巢功能的影响的能力。