X-Linked Mental Retardation-Linkage

描述（由申请人提供）： 男性比例超过 20% 至 30% 智障人口的情况是有据可查的。至少有一半 过量可能是由于 X 连锁基因的突变造成的。估计有 30-40 个位点 与非综合征性 X 连锁智力低下 (XLMR) 相关，并且一种 一百三十与特定的 XLMR 综合征相关。其中最著名的是 这就是脆性 X 综合征，但它只占 XLMR 的三分之一 家庭。由于X连锁遗传模式和目前的分子 从方法论上看，这些疾病特别适合研究。假设 需要检验的是对遗传和发病机制的充分了解 这些疾病将导致诊断和（最终）治疗的改进。的 该研究的直接目标是确定致病基因和遗传因素 通往 XLMR 的途径。此外，我们将更好地定义临床和 这些疾病的神经行为表型，每种都表现出独特的 有关大脑发育和功能的方面。过去十年，55 家大型 XLMR家庭和68个较小的家庭已被纳入基因研究 定位、基因测试和神经行为研究。三十二个 家族被定位于 X 染色体的一个离散区域。在 除了这些家族之外，还有 2 名 X 染色体倒位的男性 与智力低下有关，3名男性有小缺失 可用于分子研究。我们已经存放了三项 XLMR 研究的大脑 家庭都在迈阿密大脑银行中，并将利用它们进行分子生物学研究 研究和综合组织学分析。三位新调查员， （Srivastava、Inana 和 Warren）加入了这项研究。各种合适的 微阵列系统、消减 cDNA 和其他适当的方法（包括 最大限度地利用新的人类基因组数据）将用于识别和 描述未来五年内十到十五个 XLMR 基因的特征。我们会 每年继续接纳五个新家庭和一些较小的家庭。 神经行为研究将紧密融入临床评估 每个新的大家庭。更广泛的神经行为研究 将在三个 XLMR 实体中进行 MRI 形态测量分析： 科芬-洛瑞、ATRX 和艾伦-赫恩登综合症。总而言之，这代表了一个 独特的研究结合了多种方法和学科 更好地了解 X 染色体上的基因在大脑发育中的作用 和功能。

DESCRIPTION (provided by applicant): A 20 to 30 percent excess of males among the mentally retarded population is well documented. At least half of the excess is likely due to mutations of X-linked genes. An estimated 30-40 loci are associated with nonsyndromic X-linked mental retardation (XLMR) and one hundred thirty are associated with specific XLMR syndromes. The best known of these is the Fragile X syndrome but it accounts for only a third of XLMR families. Because of the X-linked mode of inheritance and current molecular methodologies, these disorders are especially amenable to study. The hypothesis to be tested is that a full understanding of the genetics and pathogenesis of these disorders will lead to improved diagnosis and (ultimately) therapy. The immediate goal of the study is to identify the causative genes and the genetic pathways leading to XLMR. In addition, we will better define the clinical and neurobehavioral phenotypes of these disorders, each of which presents unique aspects about brain development and function. Over the last ten years, 55 large XLMR families and 68 smaller families have been admitted to the study for gene localization, gene testing and neurobehavioral studies. Thirty-two of the families have been localized to a discrete region of the X chromosome. In addition to these families, 2 males with inversions of the X chromosome associated with mental retardation and 3 males with small deletions are available for molecular studies. We have deposited brains from three XLMR study families are in the Miami Brain Bank and will utilize them for both molecular studies and comprehensive histological analysis. Three new investigators, (Srivastava, Inana, and Warren) have joined the study. A variety of appropriate microarray systems, subtractive cDNA and other appropriate methods (including maximal utilization of the new human genorne data) will be used to identify and characterize ten to fifteen XLMR genes over the next five years. We will continue to admit five new families and a number of smaller families each year. Neurobehavioral studies will be closely integrated into the clinical evaluation of each of the new large families. More extensive neurobehavioral studies along with MRI morphometric analysis will be conducted in three XLMR entities: Coffin-Lowry, ATRX and Allan-Herndon Syndrome. In summary, this represents a unique study that combines a variety of methodologies and disciplines in order to better understand the role of genes on the X chromosome in brain development and function.