Identification of Rare Mutations of Two Presynaptic Cytomatrix Genes BSN and PCLO in Schizophrenia and Bipolar Disorder

Abstract

Schizophrenia and bipolar disorder are severe mental disorders with a major component of genetic factors in their etiology. Rare mutations play a significant role in these two disorders, and they are highly heterogeneous and personalized. Identification of personalized mutations is essential for the establishment of molecular diagnosis, providing insight into pathogenesis and guiding the personalized treatment for each affected patient. We conducted whole-genome sequencing analysis of families with schizophrenia and bipolar disorder to search for their genetic underpinnings. This report identified a rare missense mutation Arg1087Gln of BSN (bassoon presynaptic cytomatrix protein) co-segregating with schizophrenia in a family with multiple affected members. Furthermore, we identified the rare missense mutation Ser1535Leu of PCLO (piccolo presynaptic cytomatrix protein) in two sisters with bipolar disorder and another rare missense mutation, His5142Arg in PCLO, in a patient with schizophrenia. These three missense mutations were very rare and were predicted to be pathogenic. The BSN and PCLO genes encode two structurally related proteins of the presynaptic cytomatrix at the active zone that regulates neurotransmission at the presynaptic neuronal terminal. Our findings suggest the involvement of the presynaptic matrix in the pathogenesis of schizophrenia and bipolar disorder, and BSN and PCLO are the risk genes for schizophrenia and bipolar disorder.

Consensus Clustering and Survival-Related Genes of Cuproptosis in Cutaneous Melanoma

“…However, PCLO has not been reported in melanoma. It has been found that there are mutations in patients with schizophrenia, bipolar disorder, and major depression [ 46 ]. In addition, in the copy number change frequency analysis, the probability of loss of the copy of the CDKN2A gene in CRG was significantly higher than that of a gain copy.…”

Multi-Omics Analysis Reveals Myelin, Presynaptic and Nicotinate Alterations in the Hippocampus of G72/G30 Transgenic Mice

“…However, there is limited information on a potential implication of Bsn and Pclo in schizophrenia manifestation. Recently, mutations in both Pclo and Bsn genes have been identified in subjects with schizophrenia [35], whereas increased Pclo gene expression was reported in the amygdala of schizophrenia patients [36]. Furthermore, mice with suppressed Pclo expression in the medial prefrontal cortex exhibited schizophrenia-like behaviors [37].…”

Neural Extracellular Matrix Remodeling Signatures in Genetic and Acquired Mouse Models of Epilepsy

“…Initial studies have shown that Bsn-mutant mice with partial deletion of the Bassoon coding region affecting all synapses (Bsn ΔEx4/5 ) suffer from massive sensory impairment (Dick et al, 2003;Khimich et al, 2005;tom Dieck et al, 2005) and from severe, sometimes fatal epileptic seizures (Altrock et al, 2003). Meanwhile clinical evidence has accumulated that genetic variability in the human BSN gene contributes to epilepsies in patients (Conroy et al, 2014;Skotte et al, 2022;Wang et al, 2017;Ye et al, 2022) as well as to other brain disorders, including intellectual disability (Froukh, 2017), bipolar disorder, schizophrenia (Chen et al, 2021), Parkinson's Disease (Yemni et al, 2021), progressive supranuclear palsy-like syndrome and tauopathies (Martinez et al 2022;Yabe et al, 2018). Moreover, Bassoon can form intracellular aggregates in multiple sclerosis (Schattling et al, 2019) and aggravate tau seeds in tauopathies (Martinez et al, 2022), suggesting that balanced Bassoon levels are crucial for a healthy brain.…”