RSRC1, whose polymorphism is associated with altered brain function in schizophrenia, is a member of the serine and arginine rich-related protein family. Through homozygosity mapping and whole exome sequencing we show that RSRC1 mutation causes an autosomal recessive syndrome of intellectual disability, aberrant behaviour, hypotonia and mild facial dysmorphism with normal brain MRI. Further, we show that RSRC1 is ubiquitously expressed, and that the RSRC1 mutation triggers nonsense-mediated mRNA decay of the RSRC1 transcript in patients’ fibroblasts. Short hairpin RNA (shRNA)-mediated lentiviral silencing and overexpression of RSRC1 in SH-SY5Y cells demonstrated that RSRC1 has a role in alternative splicing and transcription regulation. Transcriptome profiling of RSRC1-silenced cells unravelled specific differentially expressed genes previously associated with intellectual disability, hypotonia and schizophrenia, relevant to the disease phenotype. Protein-protein interaction network modelling suggested possible intermediate interactions by which RSRC1 affects gene-specific differential expression. Patient-derived induced pluripotent stem cells, differentiated into neural progenitor cells, showed expression dynamics similar to the RSRC1-silenced SH-SY5Y model. Notably, patient neural progenitor cells had 9.6-fold downregulated expression of IGFBP3, whose brain expression is affected by MECP2, aberrant in Rett syndrome. Interestingly, Igfbp3-null mice have behavioural impairment, abnormal synaptic function and monoaminergic neurotransmission, likely correlating with the disease phenotype.

中文翻译：

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RSRC1突变通过异常的剪接和转录影响智力和行为，下调IGFBP3

RSRC1多态性与精神分裂症的脑功能改变有关，是富含丝氨酸和精氨酸的相关蛋白家族的成员。通过纯合性作图和整个外显子组测序，我们显示RSRC1突变可导致正常人的MRI导致智障，异常行为，肌张力低下和轻度面部畸形的常染色体隐性遗传综合征。此外，我们表明，RSRC1被普遍表达，并且RSRC1突变触发了患者成纤维细胞中RSRC1转录物的无意义介导的mRNA衰变。短发夹RNA（shRNA）介导的慢病毒沉默和过表达RSRC1在SH-SY5Y细胞证明RSRC1在替代剪接和转录调控中起作用。RSRC1沉默的细胞的转录组分析揭示了以前与疾病表型有关的智力残疾，低渗症和精神分裂症相关的特定差异表达基因。蛋白质-蛋白质相互作用网络建模表明，RSRC1可能通过中间相互作用影响基因特异性差异表达。患者来源的诱导性多能干细胞，分化为神经祖细胞，表现出类似于RSRC1沉默的SH-SY5Y模型的表达动态。值得注意的是，患者神经祖细胞的IGFBP3表达下调了9.6倍，其脑表达受MECP2影响，在Rett综合征中异常。有趣的是，无Igfbp3基因的小鼠有行为障碍，突触功能异常和单胺能神经传递，可能与疾病表型有关。