Genotype-Phenotype Relationships in Fragile X Families

描述(申请人提供)：在过去的两年半里，我们的研究在以下方面取得了重大突破。我们对此的理解 脆性X综合征的基因-表型关系。我们发现了一个 MRNA转化为FMR1蛋白过程中的重要翻译问题 (FMRP)，在前突变范围内开始。显著提升了。mrna 在携带前突变的男性和女性中，可以看到控制水平。 受显著影响的前突变携带者，mRNA水平可能高达 是正常的10倍，并伴有轻微的FMRP缺陷。执行职能 缺陷通常出现在带有前突变和亚群的男性中 这些50岁以上的男性表现为小脑震颤。 与脑萎缩和缓慢进行性神经认知功能下降有关。 这些问题可能与加性遗传效应和/或mRNA升高有关。 级别。我们还不知道这些神经问题在 或者这些问题是否也可能发生在 带有前置突变的年长女性。我们还有初步证据表明 脆性X综合征相关的孤独症可能与背景基因有关 效果。我们的竞争更新将集中于这两个问题： 自闭症与脆性X综合征的关系以及新出现的神经病学 表型在。携带前突变的老年携带者。我们将对这些问题进行研究 在我们的家庭研究设计(每年40个家庭)的形式下， 提供家族内的对照，并允许分析背景基因 来自我们合作者的系谱分析统计方法的效果 墨尔本拉特洛比大学的Danuta Loesch博士和Richard Huggins博士， 澳大利亚。我们将使用最先进的自闭症诊断工具，包括 孤独症诊断访谈(ADI-R)与孤独症诊断观察 量表(ADOS-G)除家庭问卷外，还评估扩展的 自闭症表型。我们将扩大家庭研究的范围，以一致地包括 祖父母和他们的兄弟姐妹更好地了解老年人的衰老过程 进行神经和神经心理评估的携带者。体积磁共振成像 研究将在有和没有震动和控制的较老的航母上进行 所有的表型发现都将与FMR1基因研究相关联，包括 MRNA、FMR1蛋白、COG重复数、甲基化状态和激活 比率除了FMR1基因研究，我们还将评估其他等位基因， 与Gerard Schellenberg博士合作，包括血清素 受体(5-HTT)和GABA受体(GABRB3)与 自闭症，以及与神经退行性变相关的ApoE和tau单倍型。

DESCRIPTION (provided by applicant): Our studies over the last 2 and a half years have lead to significant breakthroughs in. our understanding of genotype-phenotype relationships in fragile X syndrome. We have discovered a significant translation problem in the conversion of mRNA into FMR1 protein (FMRP), which begins in the premutation range. Significant elevation in. mRNA levels abo"e controls are seen in males and females with the premutation. For premutation carriers who are significantly affected, mRNA levels may be up to 10 times normal and associated with a mild FMRP deficit. Executive function deficits are usually present in males with the premutation and a subgroup of these males who are older than 50 years demonstrate a cerebellar tremor associated with brain atrophy and a slowly progressive neurocognitive decline. These problems may be related to additive genetic effects and/or elevated mRNA levels. We do not yet know the prevalence of these neurological problems in older males with the premutation, or whether these problems may also occur in older females with the premutation. We also have preliminary evidence that autism in association with fragile X syndrome may be related to background gene effects. Our competitive renewal will focus on both of these problems: the association of autism and fragile X syndrome, and the emerging neurological phenotype in. older carriers with the premutation. We will study these problems within the format of our family study design (40 families per year) which provides controls within the family and allows an analysis of background gene effects with the pedigree analysis statistical approach from our collaborators Drs. Danuta Loesch and Richard Huggins at La Trobe University in Melbourne, Australia. We will utilize state of the art autism diagnostic tools including the Autism Diagnostic Interview (ADI-R) and the Autism Diagnostic Observation scale (ADOS-G) in addition to a family questionnaire to assess the extended autism phenotype. We will expand the family studies to consistently include grandparents and their siblings to better understand the aging process in carriers with neurological and neuropsychological assessments. Volumetric MRI studies will be done on older carriers with and without tremors and controls and all phenotypic findings will be correlated with FMR1 gene studies including mRNA, FMR1 protein, COG repeat number, methylation status, and activation ratio. In addition to the FMR1 gene studies, we will assess additional alleles, in collaboration with Gerard Schellenberg, Ph.D., including the serotonin receptor (5-HTT), and the GABA receptor (GABRB3) which are associated with autism, and ApoE and tau haplotypes associated with neurodegeneration.