THE ROLE OF THE RETT GENE, CHROMOSOME 15Q11-Q13, OTHER GENES, AND EPIGENETICS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 罕见的遗传或表观遗传学疾病可以为相同或相似表型的更常见因素提供重要见解，例如对纯合家族性高胆固醇血症的研究，以及最近当单个缺失病例导致发现导致电荷综合征的基因时。少数遗传或表观遗传学条件可呈现典型的自闭症，包括MECP2突变，染色体15q11-q13内的突变，神经连接蛋白基因罕见突变，脆性X综合征和结节性硬化症。我们假设，与目前已知的相比，更多患有自闭症谱系障碍的患者具有涉及MECP2、15q11-q13染色体内的基因以及导致脆性X综合征和结节性硬化症的基因的突变或表型突变。我们还假设，与MECP2和UBE3A相互作用的基因是导致自闭症的突变或半突变的候选基因。对自闭症患者这些基因座变化的仔细研究已经导致了对自闭症的更多洞察，特别是对MECP2和15q11-q13。我们建议在这些基因和区域存在已知异常的自闭症患者中进行深入的基因/表型和表型/表型相关性，目的是进一步深入了解更常见的自闭症形式。此外，我们将分析典型的自闭症患者中涉及MECP2、15q11-q13或其他基因的新形式的突变或突变。我们将对其他自闭症候选基因进行突变和突变分析，其基础是a)解释自闭症中男性占主导地位的性别比相对于X或Y染色体上的脑或突触相关基因的可能性；或b)与MECP2、15q11-q13区域的基因、FRAXA或结节性硬化症基因的功能、生化或调节关系。 1.我们假设，与目前认识的相比，更多被诊断为自闭症谱系障碍的患者存在涉及MECP2、15q11-q13染色体上的基因以及导致脆性X综合征和结节性硬化症的基因的突变或上突变。 2.我们假设，对自闭症患者的这些基因座进行更广泛的遗传分析，特别是表观遗传学分析，将确定自闭症的新原因。 3.我们假设临床诊断为RETT或Angelman综合征的患者没有可识别的分子异常，可能分别存在涉及MECP2或UBE3A的调节性遗传或表观遗传缺陷。 4.我们假设，对已知的涉及MECP2、染色体15q11-q13和其他基因座突变或表型突变的患者进行详细的表型分析，将有助于选择和识别其他具有这些基因座异常的自闭症患者。 5.我们假设与MECP2和UBE3A相互作用的基因是导致自闭症的突变或半突变的候选基因。 6.我们假设X或Y染色体上的大脑或突触相关基因是导致自闭症的突变或表型突变的候选基因。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rare cases of genetic or epigenetic diseases can provide major insights into more common factors of the same or similar phenotypes as exemplified by studies of homozygous familial hypercholesterolemia and more recently when a single deletion case led to the discovery of a gene causing CHARGE syndrome A few genetic or epigenetic conditions can present with typical autism including mutations in MECP2, mutations within chromosome 15q11-q13, rarely mutations in neuroligin genes, fragile X syndrome, and tuberous sclerosis. We hypothesize that more patients dianosed with autism spectrum disorders have mutations or epimutations involving MECP2, genes within chromosome 15q11-q13, and the loci causing fragile X syndrome and tuberous sclerosis than is currently recognized. We also hypothesize that genes that interact with MECP2 and UBE3A are candidate genes for mutation or epimutation causing autism. Careful studies of autism patients for changes in these loci have already led to additional insights into autism, especially for MECP2 and 15q11-q13. We propose to carry out in depth genotype/phenotype and epigenotype/phenotype correlations in autistic patients with known abnormalities in these genes and regions with the goal of achieving further insights into more common forms of autism. In addition, we will anlayze typical autism patients for novel forms of mutationor epimutation involving MECP2, genes within 15q11-q13, or other genes. We will perform mutation and epimutation alalyses for other autism candidate genes based on a) potential for explaining the male predominant sex ratio in autism as for brain- or synapse-related genes on the X or Y chromosome; or b) functional, biochemical, or regulatory relationships to MECP2, genes in the 15q11-q13 region, FRAXA, or the tuberous sclerosis genes. 1. We hypothesize that more patients diagnosed with autism spectrum disorders have mutations or epimutations involving MECP2, genes within chromosome 15q11-q13, and the loci causing fragile X syndrome and tuberous sclerosis than is currently realized. 2. We hypothesize that more extensive genetic analysis and especially epigenetic analysis of these loci in autism patients will identify new causes of autism. 3. We hypothesize that patients with clinical diagnoses of Rett or Angelman syndrome without an identifiable molecular abnormality may have regulatory genetic or epigenetic defects involving the MECP2 or UBE3A, respectively. 4. We hypothesize that detailed phenotypic analysis of patients with known mutations or epimutations involving MECP2, chromosome 15q11-q13, and the other loci will allow selection and identification of additional autism patients with abnormalities of these loci. 5. We hypothesize that genes that interact with MECP2 and UBE3A are candidates for mutation or epimutation causing autism. 6. We hypothesize that brain- or synapse-related genes on the X or Y chromosome are candidates for mutations or epimutations causing autism.