PDF(Pubmed)
Abstract：
Psychosis is a severe mental disorder characterized by abnormal thoughts and perceptions (e.g., hallucinations) occurring quintessentially in schizophrenia and in several other neuropsychiatric disorders. Schizophrenia is widely considered as a neurodevelopmental disorder that onsets during teenage/early adulthood. A multiplex consanguineous Pakistani family was afflicted with severe psychosis and apparent autosomal recessive transmission. The first-cousin parents and five children were healthy, whereas two teenage daughters were severely affected. Structured interviews confirmed the diagnosis of DSM-V schizophrenia. Probands and father underwent next-generation sequencing. All available relatives were subjected to confirmatory Sanger sequencing. Homozygosity mapping and directed a priori filtering identified only one rare variant [MAF < 5(10)-5] at a residue conserved across vertebrates. The variant was a non-catalytic deubiquitinase, USP53 (p.Cys228Arg), predicted in silico as damaging. Genome sequencing did not identify any other potentially pathogenic single nucleotide variant or structural variant. Since the literature on USP53 lacked relevance to mental illness or CNS expression, studies were conducted which revealed USP53 localization in regions of the hippocampus (CA 1-3) and granular dentate. The staining pattern was like that seen with GRIA2/GluA2 and GRIP2 antibodies. All three proteins coimmunoprecipitated. These findings support the glutamate hypothesis of schizophrenia as part of the AMPA-R interactome. If confirmed, USP53 appears to be one of the few Mendelian variants potentially causal to a common-appearing mental disorder that is a rare genetic form of schizophrenia.
摘要：
精神病是一种严重的精神障碍，其特征是异常的思想和感知（例如，幻觉）典型地发生在精神分裂症和其他几种神经精神疾病中。精神分裂症被广泛认为是在青少年/成年早期发作的神经发育障碍。一个多重血缘关系的巴基斯坦家庭患有严重的精神病和明显的常染色体隐性传播。堂兄的父母和五个孩子都很健康，而两个十几岁的女儿受到严重影响。结构化访谈证实了DSM-V型精神分裂症的诊断。Probands和父亲进行了下一代测序。对所有可用的亲戚进行验证性Sanger测序。纯合性作图和定向先验过滤仅在脊椎动物保守的残基上鉴定出一个罕见的变体[MAF<5(10)-5]。该变体是一种非催化的去泛素酶，USP53（第Cys228Arg),在计算机上预测为破坏性的。基因组测序未鉴定出任何其他潜在致病性单核苷酸变体或结构变体。由于有关USP53的文献与精神疾病或中枢神经系统表达缺乏相关性，进行的研究显示USP53在海马区（CA1-3）和颗粒状齿状区域的定位。染色模式与用GRIA2/GluA2和GRIP2抗体观察到的相似。所有三种蛋白质共免疫沉淀。这些发现支持精神分裂症作为AMPA-R相互作用组的一部分的谷氨酸假说。如果确认,USP53似乎是可能导致常见的精神障碍的少数孟德尔变异之一，该精神障碍是精神分裂症的一种罕见遗传形式。
