X-Linked Mental Retardation-Linkage

描述（由申请人提供）：男性人数超过20%至30%， 关于智力迟钝人口的情况有详细的记录。至少一半的 过量可能是由于X连锁基因的突变。估计有30 - 40个位点 与非综合征性X连锁精神发育迟滞（XLMR）有关， 130例与特定的XLMR综合征相关。最有名的 这就是脆性X综合征，但它只占XLMR的三分之一 家庭由于X连锁的遗传方式和目前的分子 这些疾病特别适合研究。的假设 要测试的是，充分了解的遗传学和发病机制， 这些疾病将导致改进的诊断和（最终）治疗。的 这项研究的直接目标是确定致病基因和遗传因素， 导致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，每一种都呈现出独特的 关于大脑发育和功能。在过去的十年里， XLMR家族和68个较小的家族已被纳入基因研究。 定位、基因测试和神经行为研究。32个 家族被定位于X染色体的一个离散区域。在 除了这些家庭，2名男性与倒位的X染色体 与精神发育迟滞相关，3名男性有小缺失， 可用于分子研究。我们将三个XLMR研究中的大脑 家庭在迈阿密脑库，并将利用他们的分子 研究和全面的组织学分析。三个新的调查员， （Srivastava，Inana和Warren）加入了这项研究。各种适当的 微阵列系统、消减cDNA和其它适当的方法（包括 最大限度地利用新的人类基因组数据）将用于识别和 在接下来的五年里，我们将鉴定10到15个XLMR基因。我们将 继续每年接收五个新家庭和一些较小的家庭。 神经行为研究将与临床评价紧密结合 每一个新的大家庭。更广泛的神经行为研究沿着 将在三个XLMR实体中进行MRI形态测定分析： Coffin-Lowry、ATRX和Allan-Herndon综合征。总之，这代表了一个 独特的研究，结合了各种方法和学科， 为了更好地了解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.