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Location, frequency, and in-silico functional prediction of the three mutations identified in this study.
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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 i...
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Context 1
... allele frequency of this mutation was 0.008 in the Taiwan Biobank. In contrast, the allele frequency of this mutation was very rare in several public genome databases, including Allele Frequency Aggregator Project (ALFA), Trans-Omics for Precision Medicine Whole Genome Sequencing Project (TOPMED), and 1000 Genomes project (1000Genomes) ( Table 2). Bioinformatics analysis predicted that this mutation is deleterious to the function of PCLO (Table 2). ...Context 2
... contrast, the allele frequency of this mutation was very rare in several public genome databases, including Allele Frequency Aggregator Project (ALFA), Trans-Omics for Precision Medicine Whole Genome Sequencing Project (TOPMED), and 1000 Genomes project (1000Genomes) ( Table 2). Bioinformatics analysis predicted that this mutation is deleterious to the function of PCLO (Table 2). Under the autosomal-dominant inheritance model, we identified a G-to-A substitution at the nucleotide position 82585665 of PCLO at chromosome 7 in both sisters (CG1204 and CG1209) in the WGS analysis. ...Context 3
... allele frequency of this mutation was 0.008 in the Taiwan Biobank. In contrast, the allele frequency of this mutation was very rare in several public genome databases, including Allele Frequency Aggregator Project (ALFA), Trans-Omics for Precision Medicine Whole Genome Sequencing Project (TOPMED), and 1000 Genomes project (1000Genomes) ( Table 2). Bioinformatics analysis predicted that this mutation is deleterious to the function of PCLO (Table 2). ...Context 4
... contrast, the allele frequency of this mutation was very rare in several public genome databases, including Allele Frequency Aggregator Project (ALFA), Trans-Omics for Precision Medicine Whole Genome Sequencing Project (TOPMED), and 1000 Genomes project (1000Genomes) ( Table 2). Bioinformatics analysis predicted that this mutation is deleterious to the function of PCLO (Table 2). ...Citations
... The BSN gene encodes the Bassoon protein, a crucial component of the presynaptic cytomatrix at the active zone that facilitates synaptic vesicle trafficking. It is prominently expressed in the cerebral cortex and hippocampus regions of the mammalian brain and linked to multiple psychiatric disorders 38 . CELF4 encodes an mRNA-binding protein that regulates excitatory neurotransmission 39 . ...
Digestive and psychiatric disorders tend to co-occur, yet mechanisms remain unclear. Leveraging genetic and transcriptomic data integration, we conduct multi-trait analysis of GWAS (MTAG) and weighted gene co-expression network analysis (WGCNA) to explore shared mechanism between psychiatric and gastrointestinal disorders. Significant genetic correlations were found between these disorders, especially in irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), depression (DEP), and neuroticism (NE). MTAG identify 60 novel pleiotropic loci for IBS and 14 for GERD, predominantly located near genes associated with neurological pathways. Further WGCNA identifies multiple co-expression modules enriched with genes involved in neurological pathways in digestive tissues, with some modules strongly preserved across brain and digestive tissues. Moreover, our network analysis suggests BSN, CELF4, and NRXN1 as central players in the regulation of the gut-brain axis (GBA). This study enhances our understanding of the GBA and underscores BSN, CELF4, and NRXN1 as crucial targets for future research.
... In recent years, the involvement of BSN in several neurological diseases has been reported. 18,20,21 Presynaptic function is important in neurological diseases. ...
Clinical diagnosis of progressive supranuclear palsy (PSP) is difficult due to various phenotypes. Neuropathologically, PSP is defined by neuronal loss in the basal ganglia and brainstem with widespread occurrence of neurofibrillary tangles (NFTs) and accumulation of phosphorylated tau protein in neurons and glial cells in the brain. We previously identified the point mutation p.Pro3866Ala in the Bassoon ( BSN ) gene in a Japanese family with PSP‐like syndrome. We newly detected BSN mutations in two autopsied PSP cases carrying p.Thr2542Met and p.Glu2759Gly, respectively. The case with p.Thr2542Met mutation showed neurological symptoms including behavioral abnormalities, cognitive dysfunction, and parkinsonism. Brain magnetic resonance imaging (MRI) showed atrophy of the midbrain tegmentum and hippocampus. Pathologically, moderate to severe loss of neurons with gliosis was also found in the substantia nigra, and there was an almost complete loss of neurons with gliosis in the transitional zone of the cornu ammonis (CA) 1 region to the subiculum. NFTs were observed in the globus pallidus, subthalamic nucleus, substantia nigra, and CA1. 4R tau‐dominant tauopathy was detected. The case with p.Glu2759Gly mutation showed neurological symptoms, including right‐dominant motor impairment, right limping gait, postural instability, and cognitive dysfunction. Brain MRI showed mild atrophy of the midbrain tegmentum and left‐dominant parietal lobe atrophy. Pathologically, NFTs were detected in the globus pallidus, subthalamic nucleus, substantia nigra, thalamus, putamen, and brainstem tegmentum. Most neurons were immunopositive for four‐repeat tau, whereas only a few of them harbored three‐repeat tau‐positive NFTs in the hippocampus. We showed the results of a pathological study of PSP cases with BSN mutations; these were two new cases. The clinical phenotypes were similar to the first case in the point of neurological symptoms. Accumulation of four‐repeat tau was dominant. Further autopsies of BSN mutation cases and further elucidation of the molecular biological mechanism are desirable.
... Similarly, variants in BSN are reported to cause epilepsy in humans, a common neurological disorder featured by unprovoked seizures (Ye et al., 2023). A single nucleotide polymorphism in BSN is co-segregating with schizophrenia in a multiplex family of Taiwan (Chen et al., 2021). Furthermore, recently, a rare loss of function BSN variant has been reported to be associated with obesity in an autosomal-dominant manner (Zhu et al., 2023). ...
Background
Otitis media (OM) is the most frequent and complex middle ear condition with multifactorial etiology including genetic predisposition. OM depicts a variable clinical spectrum, leading to speech, developmental delay, and hearing loss. Here, we report the clinical and genetic findings of chronic suppurative otitis media (CSOM) segregating in a six‐generation consanguineous Pakistani family PKOM08.
Methods
Clinical evaluations, including audio and tympanometry, were conducted to assess OM manifestation and their impact on hearing function. Exome sequencing was performed to identify potential genetic variants underlying CSOM in the study participants.
Results
Clinical evaluation of participating individuals revealed varying degrees of disease severity, with mild to moderate hearing loss. All the affected individuals had CSOM with no other apparent comorbidity. Whole exome followed by Sanger sequencing revealed two rare heterozygous variants [c.1867C>T, p.(Pro623Ser) and c.11015G>A, p.(Arg3672Gln)] of BSN gene in most of the affected individuals of family PKOM08. BSN encodes a scaffold bassoon protein involved in synaptic vesicle trafficking. The identified variants replaced evolutionary conserved amino acid residues in the encoded protein and are predicted to impact the ionic interactions in the secondary structure.
Conclusion
A deep intronic variant of BSN has been previously implicated in the etiology of childhood ear infections. Our study further supports a link between BSN‐impaired function and ear infection and CSOM in children.
... The BSN protein and BSN gene were reported to be associated with multiple system atrophy (Hashida et al., 1998), Parkinson's disease (PD; Andrews and Kukkle, 2023), Huntington's disease (Huang et al., 2020), schizophrenia, bipolar disorder (Chen and Huang, 2021), multiple sclerosis (Schattling and Engler, 2019) and epilepsy (Ye et al., 2023). Gene burden analyses of rare, predicted deleterious variants provided evidence of BSN being linked to PD (Andrews and Kukkle, 2023). ...
... Other hypothesis is that the mechanism other than protein aggregation, can lead to neuronal loss. In fact, BSN mutation was also associated with various neurological diseases without protein aggregation, such as schizophrenia (Chen and Huang, 2021), multiple sclerosis (Schattling and Engler, 2019), and epilepsy (Ye et al., 2023). These reports suggest that BSN mutation may be related to the vulnerability of neurons in the central nervous system. ...
Tauopathy is known to be a major pathognomonic finding in important neurodegenerative diseases such as progressive supranuclear palsy (PSP) and corticobasal degeneration. However, the mechanism by which tauopathy is triggered remains to be elucidated. We previously identified the point mutation c.11596C > G, p.Pro3866Ala in the Bassoon gene (BSN) in a Japanese family with PSP-like syndrome. We showed that mutated BSN may have been involved in its own insolubilization and tau accumulation. Furthermore, BSN mutations have also been related to various neurological diseases. In order to further investigate the pathophysiology of BSN mutation in detail, it is essential to study it in mouse models. We generated a mouse model with the mouse Bassoon p.P3882A mutation, which corresponds to the human BSN p.P3866A mutation, knock-in (KI) and we performed systematic behavioral and histological analyses. Behavioral analyses revealed impaired working memory in a Y-maze test at 3 months of age and decreased locomotor activity in the home cage at 3 and 12 months of age in KI mice compared to those in wild-type mice. Although no obvious structural abnormalities were observed at 3 months of age, immunohistochemical studies showed elevation of Bsn immunoreactivity in the hippocampus and neuronal loss without tau accumulation in the substantia nigra at 12 months of age in KI mice. Although our mice model did not show progressive cognitive dysfunction and locomotor disorder like PSP-like syndrome, dopaminergic neuronal loss was observed in the substantia nigra in 12-month-old KI mice. It is possible that BSN mutation may result in dopaminergic neuronal loss without locomotor symptoms due to the early disease stage. Thus, further clinical course can induce cognitive dysfunction and locomotor symptoms.
... An increasing number of studies have shown that the PCLO gene variant is related to major depressive disorder and is associated with gray matter volume reduction in the left temporal lobe [20,21]. Moreover, the rare missense variants Ser1535Leu and His5142Arg of PCLO were found in patients with bipolar disorder [22]. Patients with depressive disorder are more likely to develop CAD than the general population [23,24]. ...
Objectives
The long-term prognosis of patients with coronary artery disease (CAD) with diffuse long lesion underwent coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) remains worse. Here, we aimed to identify distinctive genes involved and offer novel insights into the pathogenesis of diffuse long lesion.
Materials and methods
Whole exome sequencing was performed on peripheral blood samples from 20 CAD patients with diffuse long lesion (CAD-DLL) and from 10 controls with focal lesion (CAD-FL) through a uniform pipeline. Proteomics analysis was conducted on the serum samples from 10 CAD-DLL patients and from 10 controls with CAD-FL by mass spectrometry. Bioinformatics analysis was performed to elucidate the involved genes, including functional annotation and protein–protein interaction analysis.
Results
A total of 742 shared variant genes were found in CAD-DLL patients but not in controls. Of these, 46 genes were identified as high-frequency variant genes (≥ 4/20) distinctive genes. According to the consensus variant site, 148 shared variant sites were found in the CAD-DLL group. The lysosome and cellular senescence-related pathway may be the most significant pathway in diffuse long lesion. Following the DNA-protein combined analysis, eight genes were screened whose expression levels were altered at both DNA and protein levels. Among these genes, the MAN2A2 gene, the only one that was highly expressed at the protein level, was associated with metabolic and immune-inflammatory dysregulation.
Conclusions
Compared to individuals with CAD-FL, patients with CAD-DLL show additional variants. These findings contribute to the understanding of the mechanism of CAD-DLL and provide potential targets for the diagnosis and treatment of CAD-DLL.
... We used this technology with family analysis to explore the genetic basis for families that joined our precision psychiatry study series. We identified several rare specific variants associated with schizophrenia [25,26], affective disorders [27,28], and intellectual disability [27,29] in our previous publications, supporting the utility of this approach. This paper reports the clinical and genetic findings in two families with schizophrenia and major depressive disorder. ...
Schizophrenia and affective disorder are two major complex mental disorders with high heritability. Evidence shows that rare variants with significant clinical impacts contribute to the genetic liability of these two disorders. Also, rare variants associated with schizophrenia and affective disorders are highly personalized; each patient may carry different variants. We used whole genome sequencing analysis to study the genetic basis of two families with schizophrenia and major depressive disorder. We did not detect de novo, autosomal dominant, or recessive pathogenic or likely pathogenic variants associated with psychiatric disorders in these two families. Nevertheless, we identified multiple rare inherited variants with unknown significance in the probands. In family 1, with singleton schizophrenia, we detected four rare variants in genes implicated in schizophrenia, including p.Arg1627Trp of LAMA2, p.Pro1338Ser of CSMD1, p.Arg691Gly of TLR4, and Arg182X of AGTR2. The p.Arg691Gly of TLR4 was inherited from the father, while the other three were inherited from the mother. In family 2, with two affected sisters diagnosed with major depressive disorder, we detected three rare variants shared by the two sisters in three genes implicated in affective disorders, including p.Ala4551Gly of FAT1, p.Val231Leu of HOMER3, and p.Ile185Met of GPM6B. These three rare variants were assumed to be inherited from their parents. Prompted by these findings, we suggest that these rare inherited variants may interact with each other and lead to psychiatric conditions in these two families. Our observations support the conclusion that inherited rare variants may contribute to the heritability of psychiatric disorders.
... In humans, the gene forms part of the cytomatrix at the active zone (CAZ) complex that regulates neurotransmitter release. Other genes within the purple module connected to ERC2 gene include PCLO, RIMS1, BSN and UNC13A, all of which as associated with neurotransmitter release along the synapse [44][45][46][47][48]. A rare characteristic of RVF disease in humans is encephalitis [49]. ...
Rift Valley Fever (RVF) is a mosquito-borne viral disease caused by the Rift Valley Fever Virus. The disease is a zoonosis that largely affects domestic animals, including sheep, goats, and cattle, resulting in severe morbidity and mortality marked by massive storm abortions. To halt human and livestock deaths due to RVF, the development of efficacious vaccines and therapeutics is a compelling and urgent priority. We sought to identify potential key modules (gene clusters), hub genes, and regulatory motifs involved in the pathogenesis of RVF in Bos taurus that are amenable to inhibition. We analyzed 39 Bos taurus RNA-Seq samples using the weighted gene co-expression network analysis (WGCNA) R package and uncovered significantly enriched modules containing genes with potential pivotal roles in RVF progression. Moreover, regulatory motif analysis conducted using the Multiple Expectation Maximization for Motif Elicitation (MEME) suite identified motifs that probably modulate vital biological processes. Gene ontology terms associated with identified motifs were inferred using the GoMo human database. The gene co-expression network constructed in WGCNA using 5000 genes contained seven (7) modules, out of which four were significantly enriched for terms associated with response to viruses, response to interferon-alpha, innate immune response, and viral defense. Additionally, several biological pathways implicated in developmental processes, anatomical structure development, and multicellular organism development were identified. Regulatory motifs analysis identified short, repeated motifs whose function(s) may be amenable to disruption by novel therapeutics. Predicted functions of identified motifs include tissue development, embryonic organ development, and organ morphogenesis. We have identified several hub genes in enriched co-expressed gene modules and regulatory motifs potentially involved in the pathogenesis of RVF in B. taurus that are likely viable targets for disruption by novel therapeutics.
... , 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.All three constitutive Bsn mouse mutants develop severe epilepsy in homozygosity with high seizure-induced lethality (~50%) between 3 and 30 weeks of postnatal life. ...
Epilepsies are multifaceted neurological disorders characterized by abnormal brain activity, e.g. caused by imbalanced synaptic excitation and inhibition. The neural extracellular matrix (ECM) is dynamically modulated by physiological and pathophysiological activity and critically involved in controlling the brain's excitability. We used different epilepsy models, i.e. mice lacking the presynaptic scaffolding protein Bassoon at excitatory, inhibitory or all synapse types as genetic models for rapidly generalizing early-onset epilepsy, and intra-hippocampal kainate injection, a model for acquired temporal lobe epilepsy, to study the relationship between epileptic seizures and ECM composition. Electroencephalogram recordings revealed Bassoon deletion at excitatory or inhibitory synapses having diverse effects on epilepsy-related phenotypes. While constitutive Bsn mutants and GABAergic neuron-specific knockouts(BsnDlx5/6cKO) displayed severe epilepsy with more and stronger seizures than kainate-injected animals, mutants lacking Bassoon solely in excitatory forebrain neurons (BsnEmx1cKO) showed only mild impairments. By semiquantitative immunoblotting and immunohistochemistry we show model-specific patterns of neural ECM remodeling, and we also demonstrate significant upregulation of the ECM receptor CD44 in null and BsnDlx5/6cKO mutants. ECM-associated WFA-binding chondroitin sulfates were strongly augmented in seizure models. Strikingly, Brevican, Neurocan, Aggrecan and link protein Hapln1 levels reliably predicted seizure properties across models, suggesting a link between ECM state and epileptic phenotype.
... 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. ...
As a highly malignant tumor, the morbidity and mortality of cutaneous melanoma (CM) are increasing year by year. A novel type of cell death connected to mitochondrial metabolism is called cuproptosis. Cuproptosis regulates tumor biological behavior. Thus, genes controlling cuproptosis could be a promising candidate bioindicator for cancer therapy. Datasets of CM patients were obtained from the public database that includes clinical information and RNA-seq data. We divided CM patients into three different subgroups by unsupervised clustering method and explored the differences in functional pathways among the three subgroups by GSVA to prove the possible potential mechanism of copper death-related genes in the formation and development of CM. Secondly, we used differential analysis and Cox regression analysis to find the differential genes related to prognosis, constructed the CRG score, found the critical score for dividing high and low CRG score groups, and then analyzed the prognosis and immune infiltration of high and low CRG score groups. The results show a great correlation between OS and CRG scores. Compared with patients with high CRG scores, patients with low CRG scores have a significantly higher survival rate. In a word, copper sagging plays a certain role in the progress of CM.
... Inflammation-induced accumulation of bassoon in the central nervous systems of mice and humans boosts neurotoxic processes in multiple sclerosis [167]. A rare mutation in BSN correlates with a familial type of SCZ [168]. ...
Animal models of psychopathologies are of exceptional interest for neurobiologists because these models allow us to clarify molecular mechanisms underlying the pathologies. One such model is the inbred BTBR strain of mice, which is characterized by behavioral, neuroanatomical, and physiological hallmarks of schizophrenia (SCZ) and autism spectrum disorders (ASDs). Despite the active use of BTBR mice as a model object, the understanding of the molecular features of this strain that cause the observed behavioral phenotype remains insufficient. Here, we analyzed recently published data from independent transcriptomic and proteomic studies on hippocampal and corticostriatal samples from BTBR mice to search for the most consistent aberrations in gene or protein expression. Next, we compared reproducible molecular signatures of BTBR mice with data on postmortem samples from ASD and SCZ patients. Taken together, these data helped us to elucidate brain-region-specific molecular abnormalities in BTBR mice as well as their relevance to the anomalies seen in ASDs or SCZ in humans.
