Abstract：
MPDZ, a gene with diverse functions mediating cell-cell junction interactions, receptor signaling, and binding multivalent scaffold proteins, is associated with a spectrum of clinically heterogeneous phenotypes with biallelic perturbation. Despite its clinical relevance, the mechanistic underpinnings of these variants remain elusive, underscoring the need for extensive case series and functional investigations. In this study, we conducted a systematic review of cases in the literature through two electronic databases following the PRISMA guidelines. We selected nine studies, including 18 patients, with homozygous or compound heterozygous variants in MPDZ and added five patients from four unrelated families with novel MPDZ variants. To evaluate the role of Mpdz on hearing, we analyzed available auditory electrophysiology data from a knockout murine model (Mpdzem1(IMPC)J/em1(IMPC)J) generated by the International Mouse Phenotyping Consortium. Using exome and genome sequencing, we identified three families with compound heterozygous variants, and one family with a homozygous frameshift variant. MPDZ-related disease is clinically heterogenous with hydrocephaly, vision impairment, hearing impairment and cardiovascular disease occurring most frequently. Additionally, we describe two unrelated patients with spasticity, expanding the phenotypic spectrum. Our murine analysis of the Mpdzem1(IMPC)J/em1(IMPC)J allele showed severe hearing impairment. Overall, we expand understanding of MPDZ-related phenotypes and highlight hearing impairment and spasticity among the heterogeneous phenotypes.
摘要：
MPDZ,具有介导细胞-细胞连接相互作用的多种功能的基因，受体信号，结合多价支架蛋白，与具有双等位基因扰动的临床异质性表型谱相关。尽管它具有临床相关性，这些变体的机械基础仍然难以捉摸，强调需要进行广泛的病例系列和功能调查。在这项研究中,我们按照PRISMA指南,通过两个电子数据库对文献中的病例进行了系统回顾.我们选择了九项研究，包括18个病人,在MPDZ中具有纯合或复合杂合变体，并增加了来自四个不相关家庭的5名患者具有新的MPDZ变体。为了评估Mpdz在听力中的作用，我们分析了由国际小鼠表型分析联盟产生的敲除小鼠模型(Mpdzem1(IMPC)J/em1(IMPC)J)的听觉电生理数据.使用外显子组和基因组测序，我们确定了三个具有复合杂合变体的家族，和一个具有纯合移码变体的家族。MPDZ相关疾病在临床上是异质性的，伴有脑积水，视力障碍,听力障碍和心血管疾病发生最频繁。此外,我们描述了两个不相关的痉挛患者，扩展表型谱。我们对Mpdzem1（IMPC）J/em1（IMPC）J等位基因的鼠分析显示严重的听力障碍。总的来说,我们扩大了对MPDZ相关表型的理解,并突出了异质性表型中的听力损伤和痉挛.
