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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 遗传或表观遗传疾病的罕见病例可以提供对相同或相似表型的更常见因素的重要见解，如纯合子家族性高胆固醇血症的研究所例示的，以及最近当单个缺失病例导致发现引起CHARGE综合征的基因时。一些遗传或表观遗传疾病可以与典型的自闭症一起出现，包括MECP 2中的突变，染色体15 q11-q13内的突变，罕见的神经连接素基因突变、脆性X综合征和结节性硬化症。 我们假设，更多的自闭症谱系障碍患者有突变或表型突变，涉及MECP 2，染色体15 q11-q13内的基因，和基因座引起脆性X综合征和结节性硬化症比目前公认的。 我们还假设与MECP 2和UBE 3A相互作用的基因是导致自闭症的突变或表位突变的候选基因。 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见解，特别是MECP 2和15 q11-q13。 我们建议深入开展基因型/表型和表观基因型/表型相关性的自闭症患者与已知的异常，在这些基因和区域，以实现进一步了解更常见的形式的自闭症的目标。 此外，我们还将分析典型的自闭症患者中涉及MECP 2、15 q11-q13内的基因或其他基因的新型突变或表型突变。 我们将对其他自闭症候选基因进行突变和表观突变分析，其基础是a）解释自闭症男性占主导地位的性别比例的潜力，如X或Y染色体上的脑或突触相关基因;或B）与MECP 2、15 q11-q13区域的基因、FRAXA或结节性硬化症基因的功能、生化或调控关系。 1. 我们假设，更多的患者诊断为自闭症谱系障碍的突变或表型突变涉及MECP 2，染色体15 q11-q13内的基因，和基因座引起脆性X综合征和结节性硬化症比目前实现。 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，特别是表观遗传分析，将发现自闭症的新原因。 3. 我们假设，临床诊断为Rett或Angelman综合征而没有可识别的分子异常的患者可能分别具有涉及MECP 2或UBE 3A的调节性遗传或表观遗传缺陷。 4. 我们假设，详细的表型分析与已知的突变或表位突变涉及MECP 2，染色体15 q11-q13，和其他基因座的患者将允许选择和识别额外的自闭症患者与这些基因座的异常。 5. 我们假设与MECP 2和UBE 3A相互作用的基因是导致自闭症的突变或表位突变的候选者。 6. 我们假设X或Y染色体上的脑或突触相关基因是导致自闭症的突变或表观突变的候选者。

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.