Dataset Information

A Novel Cosegregating DCTN1 Splice Site Variant in a Family with Bipolar Disorder May Hold the Key to Understanding the Etiology.

ABSTRACT: A novel cosegregating splice site variant in the Dynactin-1 (DCTN1) gene was discovered by Next Generation Sequencing (NGS) in a family with a history of bipolar disorder (BD) and major depressive diagnosis (MDD). Psychiatric illness in this family follows an autosomal dominant pattern. DCTN1 codes for the largest dynactin subunit, namely p150Glued, which plays an essential role in retrograde axonal transport and in neuronal autophagy. A GT?TT transversion in the DCTN1 gene, uncovered in the present work, is predicted to disrupt the invariant canonical splice donor site IVS22 + 1G > T and result in intron retention and a premature termination codon (PTC). Thus, this splice site variant is predicted to trigger RNA nonsense-mediated decay (NMD) and/or result in a C-terminal truncated p150Glued protein (ct-p150Glued), thereby negatively impacting retrograde axonal transport and neuronal autophagy. BD prophylactic medications, and most antipsychotics and antidepressants, are known to enhance neuronal autophagy. This variant is analogous to the dominant-negative GLUED Gl1 mutation in Drosophila, which is responsible for a neurodegenerative phenotype. The newly identified variant may reflect an autosomal dominant cause of psychiatric pathology in this affected family. Factors that affect alternative splicing of the DCTN1 gene, leading to NMD and/or ct-p150Glued, may be of fundamental importance in contributing to our understanding of the etiology of BD as well as MDD.

SUBMITTER: Hallen A

PROVIDER: S-EPMC7231292 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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A Novel Cosegregating DCTN1 Splice Site Variant in a Family with Bipolar Disorder May Hold the Key to Understanding the Etiology.

Hallen André A Cooper Arthur J L AJL

Genes 20200418 4

A novel cosegregating splice site variant in the Dynactin-1 (DCTN1) gene was discovered by Next Generation Sequencing (NGS) in a family with a history of bipolar disorder (BD) and major depressive diagnosis (MDD). Psychiatric illness in this family follows an autosomal dominant pattern. DCTN1 codes for the largest dynactin subunit, namely p150Glued, which plays an essential role in retrograde axonal transport and in neuronal autophagy. A GT→TT transversion in the ...[more]

PMID: 32325768

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Project description:NOD‑like receptor pyrin domain‑containing 3 (NLRP3) has been considered to play a crucial role in triggering the host's immune and inflammatory responses. Genetic variants are critical determinants of interindividual variances in inflammatory responses and clinical outcomes. The role of NLRP3 gene variations in bipolar I (BPI) disorder, which is known to include genetic factors in its aetiology, has not been previously reported, at least to the best of our knowledge. The present study aimed to determine the role and frequency ofta exon 2 and exon 3 variants of NLRP3 in BPI disorder and to evaluate the association between different phenotypic traits. A case‑control study with 123 patients and 107 healthy controls was conducted to investigate the association of variants identified in the exon 2 and exon 3 regions of NLRP3, with the risk of BPI. Regions of interest were sequenced using a PCR‑based Sanger sequencing method. Three BPI‑related variants were identified. The genotype Q705K CA was detected more frequently in BPI patients, as compared to the control group [P<0.001; odds ratio (OR), 0.202; 95% confidence interval (CI), 0.080‑0.508]. In addition, two novel splice‑site variants (c.393G>A and c.278_2A>G) that, to the best of our knowledge, have not been previously reported in any database, were detected only in the BPI patient group [P<0.001; OR, 0.846; 95% CI, 0.784‑0.912; P<0.001; OR, 0.886; 95% CI, 0.832‑0.944, respectively]. There was no significant association between the Q795K variant and phenotypic traits (P>0.05). However, there was a significant association between those carrying the heterozygous c.393G>A variant and a positive family history (P=0.043). It was also observed that those with the heterozygous c.278‑2A>G variant presented with a significantly early‑onset (P=0.003). On the whole, the data of the present study suggested that NLRP3 plays a crucial role in the pathogenesis of BPI and may be a potential risk factor. However, further functional studies and repeated studies in other populations are required to properly comprehend the roles of the NLRP3 variants in the risk of developing BPI.

Project description:Background and Objectives: Depressive symptoms are prominent in both major depressive disorder (MDD) and bipolar disorder (BD). However, comparative research on the network structure of depressive symptoms in these two diagnostic groups has been limited. This study aims to compare the network structure of depressive symptoms in MDD and BD, providing a deeper understanding of the depressive symptomatology of each disorder. Materials and Methods: The Zung Self-Rating Depressive Scale, a 20-item questionnaire, was administered to assess the depressive symptoms in individuals with MDD (n = 322) and BD (n = 516). A network analysis was conducted using exploratory graph analysis (EGA), and the network structure was analyzed using regularized partial correlation models. To validate the dimensionality of the Zung SDS, principal component analysis (PCA) was adopted. Centrality measures of the depressive symptoms within each group were assessed, followed by a network comparison test between the two groups. Results: In both diagnostic groups, the network analysis revealed four distinct categories, aligning closely with the PCA results. "Depressed affect" emerged as the most central symptom in both MDD and BD. Furthermore, non-core symptoms, "Personal devaluation" in MDD and "Confusion" in BD, displayed strong centrality. The network comparison test did not reveal significant differences in the network structure between MDD and BD. Conclusions: The absence of significant differences in the network structures between MDD and BD suggests that the underlying mechanisms of depressive symptoms may be similar across these disorders. The identified central symptoms, including "Depressed affect", in both disorders and the distinct non-core symptoms in each highlight the complexity of the depressive symptomatology. Future research should focus on validating these symptoms as therapeutic targets and incorporate various methodologies, including non-metric dimension reduction techniques or canonical analysis.

Dataset Information

A Novel Cosegregating DCTN1 Splice Site Variant in a Family with Bipolar Disorder May Hold the Key to Understanding the Etiology.

Publications

A Novel Cosegregating <i>DCTN1</i> Splice Site Variant in a Family with Bipolar Disorder May Hold the Key to Understanding the Etiology.

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