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

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.

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Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

International Journal of Molecular Sciences ◽

10.3390/ijms222413189 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13189

Author(s):

Chia-Hsiang Chen ◽

Yu-Shu Huang ◽

Ting-Hsuan Fang

Keyword(s):

Bipolar Disorder ◽

Autism Spectrum ◽

Sequencing Analysis ◽

Missense Mutations ◽

Multiplex Family ◽

Rare Mutations ◽

Congenital Insensitivity ◽

Congenital Insensitivity To Pain ◽

Multiplex Families ◽

Multiple Hit

Rare mutations associated with schizophrenia (SZ) and bipolar disorder (BD) usually have high clinical penetrance; however, they are highly heterogeneous and personalized. Identifying rare mutations is instrumental in making the molecular diagnosis, understanding the pathogenesis, and providing genetic counseling for the affected individuals and families. We conducted whole-genome sequencing analysis in two multiplex families with the dominant inheritance of SZ and BD. We detected a G327E mutation of SCN9A and an A654V mutation of DPP4 cosegregating with SZ and BD in one three-generation multiplex family. We also identified three mutations cosegregating with SZ and BD in another two-generation multiplex family, including L711S of SCN9A, M4554I of ABCA13, and P159L of SYT14. These five missense mutations were rare and deleterious. Mutations of SCN9A have initially been reported to cause congenital insensitivity to pain and neuropathic pain syndromes. Further studies showed that rare mutations of SCN9A were associated with seizure and autism spectrum disorders. Our findings suggest that SZ and BD might also be part of the clinical phenotype spectra of SCN9A mutations. Our study also indicates the oligogenic involvement in SZ and BD and supports the multiple-hit model of SZ and BD.

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A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650564 ◽

1996 ◽

Vol 76 (02) ◽

pp. 253-257 ◽

Cited By ~ 14

Author(s):

Takeshi Hagiwara ◽

Hiroshi Inaba ◽

Shinichi Yoshida ◽

Keiko Nagaizumi ◽

Morio Arai ◽

...

Keyword(s):

Missense Mutation ◽

Novel Mutation ◽

Point Mutations ◽

Japanese Patients ◽

Von Willebrand Disease ◽

Homozygous Mutation ◽

Missense Mutations ◽

Reaction Products ◽

Type 3 ◽

Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

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Immunogenetic Predictors of Severe COVID-19

Vaccines ◽

10.3390/vaccines9030211 ◽

2021 ◽

Vol 9 (3) ◽

pp. 211

Author(s):

Anna Malkova ◽

Dmitriy Kudlay ◽

Igor Kudryavtsev ◽

Anna Starshinova ◽

Piotr Yablonskiy ◽

...

Keyword(s):

Genetic Factors ◽

Virus Disease ◽

Analysis Data ◽

Published Data ◽

Diagnostic Significance ◽

Life Threatening ◽

Coronavirus Infection ◽

Angiotension Converting Enzyme ◽

Related Proteins

According to an analysis of published data, only 20% of patients with the new coronavirus infection develop severe life-threatening complications. Currently, there are no known biomarkers, the determination of which before the onset of the disease would allow assessing the likelihood of its severe course. The purpose of this literature review was to analyze possible genetic factors characterizing the immune response to the new coronavirus infection that could be associated with the expression of angiotension-converting enzyme 2 (ACE-2) and related proteins as predictors of severe Corona virus disease 2019 (COVID-19). We analyzed original articles published in Medline, PubMed and Scopus databases from December 2019 to November 2020. For searching articles, we used the following keywords: New coronavirus infection, Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), COVID-19, severe course, complications, thrombosis, cytokine storm, ACE-2, biomarkers. In total, 3714 publications were selected using the keywords, of which 8 were in congruence with all the criteria. The literature analysis of the association of immunogenic characteristics and the expression of ACE-2 and related proteins with the development of severe COVID-19 revealed following genetic factors: HLA-B*46:01 genotype, CXCR6 gene hypoexpression, CCR9 gene expression, TLR7, rs150892504 mutations in the ERAP2 gene, overexpression of wild-type ACE-2, TMPRSS2 and its different polymorphisms. Genes, associated with the severe course, are more common among men. According to the analysis data, it can be assumed that there are population differences. However, the diagnostic significance of the markers described must be confirmed with additional clinical studies.

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Exploration of Alternative Splicing Events in Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells

Genes ◽

10.3390/genes12050737 ◽

2021 ◽

Vol 12 (5) ◽

pp. 737

Author(s):

Ji-Eun Jeong ◽

Binna Seol ◽

Han-Seop Kim ◽

Jae-Yun Kim ◽

Yee-Sook Cho

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Alternative Splicing ◽

Functional Enrichment ◽

Actin Binding ◽

Pcr Analysis ◽

Valuable Insight ◽

Sequencing Analysis ◽

Induced Pluripotent ◽

Insight Into

Although comparative genome-wide transcriptomic analysis has provided insight into the biology of human induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs), the distinct alternative splicing (AS) signatures of iMSCs remain elusive. Here, we performed Illumina RNA sequencing analysis to characterize AS events in iMSCs compared with tissue-derived MSCs. A total of 4586 differentially expressed genes (|FC| > 2) were identified between iMSCs and umbilical cord blood-derived MSCs (UCB-MSCs), including 2169 upregulated and 2417 downregulated genes. Of these, 164 differentially spliced events (BF > 20) in 112 genes were identified between iMSCs and UCB-MSCs. The predominant type of AS found in iMSCs was skipped exons (43.3%), followed by retained introns (19.5%), alternative 3′ (15.2%) and 5′ (12.8%) splice sites, and mutually exclusive exons (9.1%). Functional enrichment analysis showed that the differentially spliced genes (|FC| > 2 and BF > 20) were mainly enriched in functions associated with focal adhesion, extracellular exosomes, extracellular matrix organization, cell adhesion, and actin binding. Splice isoforms of selected genes including TRPT1, CNN2, and AP1G2, identified in sashimi plots, were further validated by RT-PCR analysis. This study provides valuable insight into the biology of iMSCs and the translation of mechanistic understanding of iMSCs into therapeutic applications.

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Incidence of the CHEK2 Germline Mutation and Its Impact on Clinicopathological Features, Treatment Responses, and Disease Course in Patients with Papillary Thyroid Carcinoma

Cancers ◽

10.3390/cancers13030470 ◽

2021 ◽

Vol 13 (3) ◽

pp. 470

Author(s):

Danuta Gąsior-Perczak ◽

Artur Kowalik ◽

Krzysztof Gruszczyński ◽

Agnieszka Walczyk ◽

Monika Siołek ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Missense Mutation ◽

Vascular Invasion ◽

Germline Mutations ◽

Primary Treatment ◽

Clinicopathological Characteristics ◽

Missense Mutations ◽

Papillary Thyroid ◽

Treatment Responses

The CHEK2 gene is involved in the repair of damaged DNA. CHEK2 germline mutations impair this repair mechanism, causing genomic instability and increasing the risk of various cancers, including papillary thyroid carcinoma (PTC). Here, we asked whether CHEK2 germline mutations predict a worse clinical course for PTC. The study included 1547 unselected PTC patients (1358 women and 189 men) treated at a single center. The relationship between mutation status and clinicopathological characteristics, treatment responses, and disease outcome was assessed. CHEK2 mutations were found in 240 (15.5%) of patients. A CHEK2 I157T missense mutation was found in 12.3%, and CHEK2 truncating mutations (IVS2 + 1G > A, del5395, 1100delC) were found in 2.8%. The truncating mutations were more common in women (p = 0.038), and were associated with vascular invasion (OR, 6.91; p < 0.0001) and intermediate or high initial risk (OR, 1.92; p = 0.0481) in multivariate analysis. No significant differences in these parameters were observed in patients with the I157T missense mutation. In conclusion, the CHEK2 truncating mutations were associated with vascular invasion and with intermediate and high initial risk of recurrence/persistence. Neither the truncating nor the missense mutations were associated with worse primary treatment response and outcome of the disease.

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Novel insight into the non-coding repertoire through deep sequencing analysis

Nucleic Acids Research ◽

10.1093/nar/gks228 ◽

2012 ◽

Vol 40 (11) ◽

pp. e86-e86 ◽

Cited By ~ 13

Author(s):

Ofer Isakov ◽

Roy Ronen ◽

Judit Kovarsky ◽

Aviram Gabay ◽

Ido Gan ◽

...

Keyword(s):

Deep Sequencing ◽

Sequencing Analysis ◽

Deep Sequencing Analysis ◽

Insight Into

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Structure and function of factor XI

Blood ◽

10.1182/blood-2009-09-199182 ◽

2010 ◽

Vol 115 (13) ◽

pp. 2569-2577 ◽

Cited By ~ 118

Author(s):

Jonas Emsley ◽

Paul A. McEwan ◽

David Gailani

Keyword(s):

Catalytic Domain ◽

Structural Features ◽

Factor Ix ◽

Missense Mutations ◽

Factor Xi ◽

Disk Structure ◽

Ligand Binding Sites ◽

And Function ◽

Insight Into

AbstractFactor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX. Although bleeding associated with FXI deficiency is relatively mild, there has been resurgence of interest in FXI because of studies indicating it makes contributions to thrombosis and other processes associated with dysregulated coagulation. FXI is an unusual dimeric protease, with structural features that distinguish it from vitamin K–dependent coagulation proteases. The recent availability of crystal structures for zymogen FXI and the FXIa catalytic domain have enhanced our understanding of structure-function relationships for this molecule. FXI contains 4 “apple domains” that form a disk structure with extensive interfaces at the base of the catalytic domain. The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets. Analyses of missense mutations associated with FXI deficiency have provided additional clues to localization of ligand-binding sites on the protein surface. Together, these data will facilitate efforts to understand the physiology and pathology of this unusual protease, and development of therapeutics to treat thrombotic disorders.

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Converging physiological roles of the anthrax toxin receptors

F1000Research ◽

10.12688/f1000research.19423.1 ◽

2019 ◽

Vol 8 ◽

pp. 1415

Author(s):

Oksana A. Sergeeva ◽

F. Gisou van der Goot

Keyword(s):

Anthrax Toxin ◽

Loss Of Function ◽

Disease Symptoms ◽

Hyaline Fibromatosis Syndrome ◽

Anthrax Toxins ◽

The Difference ◽

Related Proteins ◽

Tumor Endothelial Marker 8 ◽

Insight Into ◽

Shed Light

The anthrax toxin receptors—capillary morphogenesis gene 2 (CMG2) and tumor endothelial marker 8 (TEM8)—were identified almost 20 years ago, although few studies have moved beyond their roles as receptors for the anthrax toxins to address their physiological functions. In the last few years, insight into their endogenous roles has come from two rare diseases: hyaline fibromatosis syndrome, caused by mutations in CMG2, and growth retardation, alopecia, pseudo-anodontia, and optic atrophy (GAPO) syndrome, caused by loss-of-function mutations in TEM8. Although CMG2 and TEM8 are highly homologous at the protein level, the difference in disease symptoms points to variations in the physiological roles of the two anthrax receptors. Here, we focus on the similarities between these receptors in their ability to regulate extracellular matrix homeostasis, angiogenesis, cell migration, and skin elasticity. In this way, we shed light on how mutations in these two related proteins cause such seemingly different diseases and we highlight the existing knowledge gaps that could form the focus of future studies.

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GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension

Journal of Experimental Medicine ◽

10.1084/jem.20201745 ◽

2021 ◽

Vol 218 (7) ◽

Author(s):

Kaela Drzewiecki ◽

Jungmin Choi ◽

Joseph Brancale ◽

Michael A. Leney-Greene ◽

Sinan Sari ◽

...

Keyword(s):

Endothelial Cells ◽

Portal Hypertension ◽

Liver Disease ◽

Endothelial Cell ◽

Sequencing Analysis ◽

Major Contributor ◽

Liver Sinusoidal Endothelial Cells ◽

Cell Homeostasis ◽

Liver Endothelial Cell ◽

Insight Into

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

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Use of antipsychotic drugs and mood stabilizers in women of childbearing age with schizophrenia and bipolar disorder: epidemiological survey

Epidemiology and Psychiatric Sciences ◽

10.1017/s2045796013000012 ◽

2013 ◽

Vol 22 (4) ◽

pp. 355-361 ◽

Cited By ~ 10

Author(s):

C. Barbui ◽

V. Conti ◽

M. Purgato ◽

A. Cipriani ◽

I. Fortino ◽

...

Keyword(s):

Bipolar Disorder ◽

Epidemiological Survey ◽

Mood Stabilizers ◽

Administrative Databases ◽

Health Concern ◽

Women Of Childbearing Age ◽

Childbearing Age ◽

Severe Mental Disorders ◽

Normal Delivery ◽

Drug Treatments

Aims.To determine the prevalence of women of childbearing age with schizophrenia and bipolar disorder exposed to antipsychotic (AP) drugs and mood stabilizers (MS) in Lombardy, a European region of 10 million inhabitants and 1 752 285 women of childbearing age.Methods.The data concerning psychiatric care, drug treatments and pregnancy outcomes were retrieved from local administrative databases during a 12-month census period.Results.During a 12-month census period, 2893 women of childbearing age with schizophrenia (74.8% of all women of childbearing age with schizophrenia) and 918 with bipolar disorder (80.1% of all women of childbearing age with bipolar disorder) were exposed to AP drugs or MS, yielding a prevalence of exposure for women with schizophrenia of 1.65 (95% confidence interval (CI) 1.59–1.71) per 1000 female inhabitants, and for women with bipolar disorder of 0.52 (95% CI 0.49–0.55) per 1000 female inhabitants. Persistent exposure to potentially teratogenic medications accounted for one in every 1000 women of childbearing age. Of the 57 pregnancies in women with schizophrenia, normal delivery was recorded in 23 (40%) cases; of the 26 pregnancies in women with bipolar disorder, normal delivery was recorded in 10 (38%) cases.Conclusions.In women of childbearing age with severe mental disorders, exposure to psychotropic drugs is substantial, which suggests that the issue of reproductive health is epidemiologically relevant and a major public health concern.

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