MOLECULAR GENETICS OF 15Q11-Q13 DEFECTS IN AUTISM

自闭症是一种严重的神经发育障碍，其特征是社交和语言障碍，以及行为异常，包括重复或刻板印象的行为。自闭症很常见，影响大约2-5/10000的儿童，并经常伴随着精神发育迟缓和癫痫等神经特征。自闭症有一个复杂的病因，来自系谱、双胞胎和兄弟姐妹研究的证据表明，有很强的遗传因素。两类研究指出，在Prader-Willi综合征和Angelman综合征(AS)中缺失的染色体15q11-q13区域是自闭症的一个或多个基因座。在自闭症人群中持续检测到影响母系起源的染色体并导致三到四个拷贝的15q11-q13的大重复；这意味着基因组印记的潜在作用，并可能表明该区域正常的、可能印记的基因剂量的破坏可能导致自闭症的易感性。独立研究支持多胎家庭中的自闭症与15q11-q13的联系，以及自闭症家庭中15q11-q13母体重组热点的增加。用于连锁研究的DNA标记基因分型显示，在自闭症家系中，在15q11-q13的几个标记上存在零和三个等位基因类型，这表明较小的基因组重排。我们的特征是包含一个标记的5kb基因组缺失是导致这些结果的原因，与对照组相比，这种缺失在自闭症家族中出现的频率明显更高，这表明两者之间存在关联。这一潜在的易感标记将被进一步探索与自闭症的相关性。大量复制的母体特异性可能直接指向印记的、母体表达的基因，被称为UBE3A的AS基因就是一个例子。然而，连锁和相关数据似乎表明，在包含多个神经和位置候选基因以及未解决的印记状态的区域内，自闭症基因座的端粒位置略有增加。联合复制和连锁数据可能涉及一个可能的多态易感等位基因。该项目将把关键区域的基因组序列和重叠群、大复制和小缺陷、基因、简单序列重复标记和正在形成的多态联系起来。自闭症候选区域的基因将被分析在大脑中的表达和印记，筛选功能序列变异，并在单链和多链家族中分析变异，以测试是否与自闭症有关。

Autism is a severe neurodevelopmental disorder characterized by social interaction and language deficits, and behavior abnormalities, including repetitive or stereotyped actions. Autism is common, affects approximately 2-5/10000 children, and is often seen with accompanying neurological features such as mental retardation and seizures. Autism has a complex etiology, with evidence from pedigree, twin and sibling studies indicating a strong genetic component. Two categories of investigation point to the chromosome 15q11-q13 region deleted in Prader-Willi syndrome and Angelman syndrome (AS) as harboring a locus or loci for autism. Large duplications, affecting maternally-derived chromosomes and resulting in three or four copies of 15q11-q13, are consistently detected in the autistic population; this implies a potential role of genomic imprinting and may indicate that disruption of normal, possibly imprinted , gene dosage of this region can confer susceptibility to autism. Independent studies support linkage of autism in multiplex families to 15q11- q13 and elevated recombination in a 15q11-q13 maternal recombination hotspot, in autism families. DNA marker genotyping for linkage studies reveals null and three allele genotypes at several markers within 15q11-q13, in autism families, suggesting smaller genomic rearrangements. We characterize a 5-kb genomic deletion encompassing one marker as a cause for these results, and this deletion is present at a significantly higher frequency in autism families compared to controls, suggesting an association. This potential susceptibility marker will be explored further for relevance to autism. Maternal-specificity of large duplications may point directly to imprinted, maternally-expressed genes, of which the AS gene termed UBE3A, is an example. The linkage and related data, however, appear to indicate a slightly more telomeric location for an autism locus, within a region containing multiple neurological and positional candidates and unresolved imprinting status. Uniting the duplication and linkage data could involve a possible hypermorphic susceptibility allele. The project will correlate genomic sequence and contigs for the key region, with large duplications and smaller defects, genes, simple-sequence repeat markers, and developing polymorphisms. Genes in the autism candidate region will be analyzed for expression and imprinting in the brain, screened for functional sequence variation, and variants analyzed in simplex and multiplex families to test for involvement in autism.