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Open AccessArticle

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

1
Department of Molecular Sciences, Macquarie University, Sydney 2109, NSW, Australia
2
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
*
Authors to whom correspondence should be addressed.
Genes 2020, 11(4), 446; https://doi.org/10.3390/genes11040446
Received: 10 March 2020 / Revised: 8 April 2020 / Accepted: 15 April 2020 / Published: 18 April 2020
(This article belongs to the Special Issue Genetics of Psychiatric Disorders)
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. View Full-Text
Keywords: Bipolar disorder genetics; DCTN1; p150Glued; retrograde axonal transport; autophagy Bipolar disorder genetics; DCTN1; p150Glued; retrograde axonal transport; autophagy
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Hallen, A.; Cooper, A.J.L. A Novel Cosegregating DCTN1 Splice Site Variant in a Family with Bipolar Disorder May Hold the Key to Understanding the Etiology. Genes 2020, 11, 446.

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