Association of genetic variations in <i>DTNBP1</i> with cognitive function in schizophrenia patients and healthy subjects

Baek, Ji Hyun; Kim, Ji Sun; Ryu, Seunghyong; Oh, Sohee; Noh, Jihae; Lee, Woo Kyeong; Park, Taesung; Lee, Yu-Sang; Lee, Dongsoo; Kwon, Jun Soo; Hong, Kyung Sue

doi:10.1002/ajmg.b.32091

Cited by 15 publications

(11 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies have investigated the role of this gene in cognitive deficits of schizophrenia. For example, DTNBP1 haplotypes are associated with greater decline in IQ (Burdick et al, 2007) and impairment in spatial working memory (Donohoe et al, 2007;Donohoe et al, 2008;Donohoe et al, 2010) and attentional/vigilance (Baek et al, 2012), verbal and visual working memory and speed of processing (Varela-Gomez et al, 2015), as well as executive function (Scheggia et al, 2018). Such findings have been less evident on subdividing schizophrenia patients into cognitive-deficit and cognitivesparing groups (Peters et al, 2008).…”

Section: Schizophrenia Cognitive Impairment and Variation In Dtnbp1mentioning

confidence: 99%

Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond

2020

View full text Add to dashboard Cite

Alongside positive and negative symptomatology, deficits in working memory, attention, selective learning processes, and executive function have been widely documented in schizophrenia spectrum psychosis. These cognitive abnormalities are strongly associated with impairment across multiple function domains and are generally treatment-resistant. The DTNBP1 (dystrobrevin-binding protein-1) gene, encoding dysbindin, is considered a risk factor for schizophrenia and is associated with variation in cognitive function in both clinical and nonclinical samples. Downregulation of DTNBP1 expression in dorsolateral prefrontal cortex and hippocampal formation of patients with schizophrenia has been suggested to serve as a primary pathophysiological process. Described as a "hub," dysbindin is an important regulatory protein that is linked with multiple complexes in the brain and is involved in a wide variety of functions implicated in neurodevelopment and neuroplasticity. The expression pattern of the various dysbindin isoforms (-1A,-1B,-1C) changes depending upon stage of brain development, tissue areas and subcellular localizations, and can involve interaction with different protein partners. We review evidence describing how sequence variation in DTNBP1 isoforms has been differentially associated with schizophrenia-associated symptoms. We discuss results linking these isoform proteins, and their interacting molecular partners, with cognitive dysfunction in schizophrenia, including evidence from drosophila through to genetic mouse models of dysbindin function. Finally, we discuss preclinical evidence investigating the antipsychotic potential of molecules that influence dysbindin expression and functionality. These

show abstract

Section: Schizophrenia Cognitive Impairment and Variation In Dtnbp1mentioning

confidence: 99%

Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond

2020

View full text Add to dashboard Cite

show abstract

“…Several single SNPs of DTNBP1 were suggested to influence multiple psychiatric phenotypes in schizophrenic patients. For example: (i) SNP rs1997679 and SNP rs9370822 were proven to be associated with visual hallucination [ 65 ]; (ii) SNP rs4236167 was associated with auditory hallucination [ 65 ]; (iii) SNP rs9370822 and SNP rs9370822 were found associated with olfactory hallucinations [ 65 ]; (iv) SNP rs909706, rs760761 and rs1018381 were associated with attention [ 66 , 67 ]; (v) SNP rs2619522 was correlated with hippocampal and prefrontal grey matter volumes in schizophrenic patients [ 68 ]; and (vi) SNP rs9370822 affected glutamatergic or dopaminergic neurotransmission and has been found to be associated with a number of psychiatric conditions including schizophrenia [ 69 ]. In 2014, Schizophrenia Working Group of the Psychiatric Genomics Consortium reported a multi-stage schizophrenia genome-wide association study of more than 150,000 people and found 108 schizophrenia-associated genetic loci [ 70 ].…”

Section: Association Of Dysbindin-1 With Schizophreniamentioning

confidence: 99%

Dysbindin-1 Involvement in the Etiology of Schizophrenia

Wang

Lazarovici

Zheng

2017

IJMS

View full text Add to dashboard Cite

Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world’s population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia.

show abstract

“…These regions are essential elements in a hippocampal-prefrontal cortical network that is implicated in the regulation not only of memory, emotion, and other selfreferential processes (Aggleton, 2012) but also of putative sexually dimorphic cognitive dysfunction in schizophrenia (Mendrek and Mancini-Marie, 2015). Indeed, the role of dysregulated dysbindin-1 gene and protein expression in schizophrenia appears most closely related to the prominent cognitive impairment in that disorder as DTNBP1 genotype influences cognition both in normal subjects and in schizophrenia (Burdick et al, 2007;Zinkstok et al, 2007;Zhang et al, 2010;Wolf et al, 2011;Baek et al, 2012;Varela-Gomez et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of Specialized Delay/Interference-Dependent Working Memory Following Loss of Dysbindin-1A in Schizophrenia-Related Phenotypes

Petit

Michalak

Cox

et al. 2016

Neuropsychopharmacol

View full text Add to dashboard Cite

Dysbindin-1, a protein that regulates aspects of early and late brain development, has been implicated in the pathobiology of schizophrenia. As the functional roles of the three major isoforms of dysbindin-1, (A, B, and C) remain unknown, we generated a novel mutant mouse, dys-1A, with selective loss of dysbindin-1A and investigated schizophrenia-related phenotypes in both males and females. Loss of dysbindin-1A resulted in heightened initial exploration and disruption in subsequent habituation to a novel environment, together with heightened anxiety-related behavior in a stressful environment. Loss of dysbindin-1A was not associated with disruption of either long-term (olfactory) memory or spontaneous alternation behavior. However, dys-1A showed enhancement in delay-dependent working memory under high levels of interference relative to controls, ie, impairment in sensitivity to the disruptive effect of such interference. These findings in dys-1A provide the first evidence for differential functional roles for dysbindin-1A vs dysbindin-1C isoforms among phenotypes relevant to the pathobiology of schizophrenia. Future studies should investigate putative sex differences in these phenotypic effects.

show abstract

Association of genetic variations in DTNBP1 with cognitive function in schizophrenia patients and healthy subjects

Cited by 15 publications

References 52 publications

Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond

Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond

Dysbindin-1 Involvement in the Etiology of Schizophrenia

Dysregulation of Specialized Delay/Interference-Dependent Working Memory Following Loss of Dysbindin-1A in Schizophrenia-Related Phenotypes

Contact Info

Product

Resources

About