Functional characterization of a FRMPD4 mutation in a UDP family

描述（由申请人提供）：摘要NIH未诊断疾病项目（UDP）的重点是定义罕见遗传疾病的分子基础和机制。申请UPD项目的大部分患者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。X连锁基因FRMPD 4（也称为Preso 1）的错义突变最近在两个男性同胞中被发现，他们表现出全面发育迟缓，认知退化，癫痫发作障碍和其他临床发现的一系列。在这里，我们将检验人类Preso 1-K195 E是这些症状的因果关系的假设。在我们以前的工作中，我们已经确定Preso 1作为一个共同的功能蛋白与1组代谢型谷氨酸受体（mGluR）。已知组1 mGluR信号传导的遗传修饰导致小鼠模型中的各种发育和退行性表型（Niswender和Conn，2010）。Preso 1编码结合mGluR 5并控制其磷酸化状态的多结构域蛋白，从而提供mGluR 5功能的重要调节。我们建议利用体外和基于神经元的测定，并产生转基因小鼠模型来检验以下假设：Preso 1的K187 E小鼠突变导致mGluR 5功能改变，这对突触形成、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mGluR 5功能的发育性脑疾病的其他遗传原因的会聚机制，包括脆性X智力低下综合征。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Preso 1（K195 E）是否是UDP家族神经缺陷的原因，以及Preso基因家族是否代表发育性大脑疾病的新原因。这些结果将为建立合理的治疗方法提供重要的发病机制。

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.