Delineation of genetic pathomechanisms underlying severe intellectual disability related to Pitt-Hopkins syndrome

描述与皮特-霍普金斯综合征相关的严重智力障碍的遗传病理机制

• 批准号: 123849860
• 负责人: Professorin Dr. Christiane Zweier
• 金额: --
• 依托单位: Abteilung für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/123849860?language=en
• 关键词: Delineation; genetic; pathomechanisms; underlying; severe

Following our identification of TCF4 haploinsufficiency as the underlying cause for Pitt-Hopkins syndrome, which is associated with severe ID and variable other anomalies, many patients with this suspected diagnosis were referred to our group for TCF4 testing. In various patients without TCF4 mutation, molecular karyotyping enabled us to identify several defects in NRXN1 or CNTNAP2. By utilizing Drosophila melanogaster as a model organism we found indication of a functional interaction between NRXN1 and CNTNAP2. This common molecular basis might provide an explanation for the similar clinical phenotype in the patients. In order to identify further novel genes in our cohort of patients with severe intellectual disability resembling Pitt-Hopkins syndrome, but without mutations in the known genes, we will utilize whole-exome sequencing in trios of patients and their parents. Furthermore, we will continue to use Drosophila melanogaster to functionally characterize the novel genes and investigate molecular interactions between all genes involved. This will help delineate a molecular link as the basis for the phenotypic overlap and to establish a possible starting point for future interventional strategies.

在我们确定TCF 4单倍不足是Pitt-Hopkins综合征的潜在原因后，许多疑似诊断的患者被转诊到我们的小组进行TCF 4检测。在没有TCF 4突变的各种患者中，分子核型分析使我们能够识别NRXN 1或CNTNAP 2中的几种缺陷。通过利用果蝇作为模式生物，我们发现NRXN 1和CNTNAP 2之间的功能相互作用的迹象。这种共同的分子基础可能为患者相似的临床表型提供了解释。为了在我们的患有类似Pitt-Hopkins综合征的严重智力残疾但已知基因没有突变的患者队列中进一步鉴定新基因，我们将在患者及其父母的三人组中利用全外显子组测序。此外，我们将继续使用果蝇的功能特性的新基因，并调查所有相关基因之间的分子相互作用。这将有助于描绘一个分子联系的基础上的表型重叠，并建立一个可能的起点，为未来的干预策略。

项目成果

Altered GPM6A/M6 Dosage Impairs Cognition and Causes Phenotypes Responsive to Cholesterol in Human and Drosophila

• DOI: 10.1002/humu.22697
• 发表时间: 2014-12-01
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Gregor, Anne;Kramer, Jamie M.;Zweier, Christiane
• 通讯作者: Zweier, Christiane

Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum

• DOI: 10.1136/jmedgenet-2016-103880
• 发表时间: 2016-12-01
• 期刊: JOURNAL OF MEDICAL GENETICS
• 影响因子: 4
• 作者: Smogavec, Mateja;Cleall, Alison;Zweier, Christiane
• 通讯作者: Zweier, Christiane