GENETIC STUDIES OF ODDD

奇数的遗传学研究

• 批准号: 6723853
• 负责人: Ethylin Wang Jabs
• 金额: $ 38.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6723853
• 关键词: Xenopus oocyte; autosomal dominant trait; calcium flux; calcium indicator; chimeric proteins; clinical research; congenital oral /facial /cranial defect; developmental genetics; electrophysiology; gap junctions; genetic disorder; genetically modified animals; human subject; laboratory mouse; membrane channels; molecular pathology; patient oriented research; pleiotropism; protein localization; transfection

DESCRIPTION (provided by applicant): Oculodentodigital dysplasia (ODDD) is a syndrome with an autosomal dominant pattern of inheritance, high penetrance, and variable expressivity. The phenotype includes dental, craniofacial, ocular, hand, and foot abnormalities. Central nervous system signs and symptoms related to white matter degeneration, palmar and plantar keratoderma, and cardiac abnormalities occur in some ODDD patients. Our laboratory recently identified mutations (missense and small duplication) in the gap junction protein GJA1, also referred to as connexin 43, in ODDD patients. This connexin and other connexin proteins are known to form connexons that align as pairs in apposing cell membranes to form specialized intercellular gap junctions. These channels confer distinct physiologic properties by providing an intercellular passage for ions and small molecules. Identification of this disease gene now allows us to study the pathophysiology of ODDD at the molecular level. The goal of this application is to investigate the functional changes in the mutant protein and correlate these effects to the phenotypic features observed in this condition. The following hypotheses will be tested: 1) The GJA1 mutations found in ODDD patients alter the function of the mutant allele and causes aberrant gap junction channels to form. These aberrant connexons lead to lack of gap junction formation or to gap junctions that are functionally altered. 2) GJA1 mutations alter gap junction intercellular communication of calcium signaling via mutant connexin 43 hemichannels. 3) The phenotypic pleiotropy observed in ODDD are due to interactions among the mutant connexin 43 and other members of the connexin protein family that alter expression or heterotypic pairings of connexons in affected tissues. Cellular transfection studies, utilizing mammalian cells and Xenopus oocytes, and creation of mutant GJA1 transgenic mice with alterations analogous to the mutations found in patients will serve as model systems to study embryonic and pathophysiologic aspects of ODDD. The information generated by these developmental and functional studies will increase our understanding of the normal process of craniofacial and dental development, as well as of other abnormal processes including postnatal neurodegeneration.

描述（由申请人提供）：眼齿指发育不良（ODDD）是一种具有常染色体显性遗传模式、高外显率和可变表达性的综合征。表型包括牙齿、颅面、眼部、手部和足部异常。一些 ODDD 患者会出现与白质变性、手掌和足底角化病以及心脏异常相关的中枢神经系统体征和症状。我们的实验室最近在 ODDD 患者中发现了间隙连接蛋白 GJA1（也称为连接蛋白 43）的突变（错义和小重复）。已知这种连接蛋白和其他连接蛋白形成连接子，这些连接子在并置细胞膜中成对排列以形成专门的细胞间间隙连接。这些通道通过为离子和小分子提供细胞间通道而赋予独特的生理特性。该疾病基因的鉴定现在使我们能够在分子水平上研究 ODDD 的病理生理学。该应用的目的是研究突变蛋白的功能变化，并将这些影响与在此条件下观察到的表型特征相关联。将测试以下假设：1) ODDD 患者中发现的 GJA1 突变改变了突变等位基因的功能并导致异常间隙连接通道的形成。这些异常的连接子导致间隙连接形成的缺乏或间隙连接的功能发生改变。 2) GJA1 突变通过突变连接蛋白 43 半通道改变钙信号传导的间隙连接细胞间通讯。 3) ODDD 中观察到的表型多效性是由于突变连接蛋白 43 和连接蛋白家族其他成员之间的相互作用，改变了受影响组织中连接子的表达或异型配对。利用哺乳动物细胞和非洲爪蟾卵母细胞进行细胞转染研究，并创建具有与患者中发现的突变类似的突变 GJA1 转基因小鼠，将作为模型系统来研究 ODDD 的胚胎和病理生理学方面。这些发育和功能研究产生的信息将增加我们对颅面和牙齿发育正常过程以及包括产后神经变性在内的其他异常过程的理解。