Functional characterization of a FRMPD4 mutation in a UDP family

描述（由申请人提供）：摘要美国国立卫生研究院未确诊疾病项目（UDP）专注于定义罕见遗传疾病的分子基础和机制。申请UPD项目的患者中有很大一部分患有未知的神经系统疾病（43%），这强调了通过临床和基础研究人员之间的密切合作开发新的诊断检查和治疗的重要性。最近在两个男性同胞中发现了x连锁基因FRMPD4（也称为Preso1）的错义突变，这两个男性同胞表现出全面发育迟缓、认知衰退、癫痫发作和一系列其他临床表现。在这里，我们将检验人类Preso1-K195E是导致这些症状的原因的假设。在我们之前的工作中，我们已经确定Preso1是与1组代谢性谷氨酸受体（mGluR）共功能的蛋白。已知在小鼠模型中，1组mGluR信号的遗传修饰会导致各种发育和退行性表型（Niswender and Conn, 2010）。Preso1编码一种结合mGluR5并控制其磷酸化状态的多结构域蛋白，从而对mGluR5的功能起到重要调控作用。我们建议利用体外实验和基于神经元的实验，并建立转基因小鼠模型来检验假设，即K187E小鼠Preso1突变导致mGluR5功能改变，而mGluR5功能对突触形成、突触可塑性和社会互动中的行为反应以及对学习和记忆重要的奖励刺激至关重要。我们将研究影响mGluR5功能的发育性脑疾病的其他遗传原因的趋同机制，包括脆性X智力迟钝综合征。我们还将在其他x连锁智力残疾和/或癫痫患者中筛查Preso基因家族成员的突变。这些研究将确定Preso1 （K195E）是否是UDP家族神经缺陷的原因，以及Preso基因家族是否代表了发育性脑疾病的新原因。这些结果将为建立合理的治疗方法提供机制上的见解。

DESCRIPTION (provided by applicant): Abstract The NIH-undiagnosed disease program (UDP) focuses on defining the molecular basis and mechanisms of rare genetic disorders. A large fraction of patients applying for the UPD program suffer from unknown neurological disorders (43%), which underscores the importance to develop novel diagnostic workup and therapies through close collaborations between clinical and basic investigators. A missense mutation in an X-linked gene, FRMPD4 (also termed Preso1), was recently identified in two male sibs who exhibited global developmental delays, cognitive regression, seizure disorders, and a constellation of other clinical findings. Here, we will examine the hypothesis that human Preso1-K195E is causal for these symptoms. In our previous work, we have identified Preso1 as a co-functional protein with the group 1 metabotropic glutamate receptors (mGluR). Genetic modifications of group 1 mGluR signaling are known to result in various developmental and degenerative phenotypes in mouse models (Niswender and Conn, 2010). Preso1 encodes a multi-domain protein that binds mGluR5 and controls its phosphorylation state, and thereby provides important regulation of mGluR5 function. We propose to utilize in vitro and neuron- based assays, and to generate transgenic mouse models to examine the hypothesis that the K187E mouse mutation of Preso1 results in altered mGluR5 functions that are crucial for synapse formation, synaptic plasticity, and behavioral responses in social interaction and to rewarding stimuli that are important for learning and memory. We will examine convergent mechanisms with other genetic causes of developmental brain disease that impact mGluR5 function including Fragile X Mental Retardation Syndrome. We will also screen for mutations in the Preso gene family members in additional patients with X-linked intellectual disability and/or epilepsy. These studies will determine if Preso1 (K195E) is causal for the neurological defects in the UDP family and if the Preso gene family represents a novel cause for developmental brain disorders. The results will provide mechanistic insights into pathogenesis that will be important for the establishment of rational therapies.