Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte\u2013myelin dysfunction

Mark E Bastin,Siddharthan Chandran,Samantha K Barton,Steffen Mayerl ,Owen Dando,Douglas Blackwood ,Kyriakos D Economides ,Paraskevi Makedonopolou,Andrew M Mcintosh,Matthew R Livesey,Charles Ffrench‐Constant ,Ellen Grünewald,Dario Magnani,J Kirsty Millar,Navneet A Vasistha,Giles E Hardingham,Dj Wyllie ,Mandy Johnstone,Stephen M Lawrie,Pippa A Thomson,Clara Alloza,Bhuvaneish T Selvaraj ,David Story ,Karen Burr

doi:10.1038/s41380-019-0505-2

Abstract

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte–myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte–myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption of white matter integrity compared with familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) derived case oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced when compared with controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte–myelin dysfunction.

Highlights

IntroductionSchizophrenia (SZ) and other major mental illnesses (MMI) such as bipolar disorder and major depression show high heritability
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Schizophrenia (SZ) and other major mental illnesses (MMI) such as bipolar disorder and major depression show high heritability
To study the impact of t(1;11) translocation on global white matter structure and structural connectivity, we undertook whole-brain probabilistic tractography using diffusion MRI (dMRI) on 21 individuals from the previously reported Scottish family known to carry the t(1:11) translocation of whom eight were carriers of the t(1;11) translocation [27]

Summary

Introduction

Schizophrenia (SZ) and other major mental illnesses (MMI) such as bipolar disorder and major depression show high heritability. Rare genetic variants, such as a balanced chromosomal translocation in a large Scottish family, that co-segregate with MMI show high penetrance [2,3,4,5,6]. The range of psychiatric phenotypes observed in people carrying the balanced t(1:11) translocation suggests its study will be of considerable value for an improved understanding of biological processes underlying MMI. This translocation disrupts the DISC1 gene and segregates with SZ and affective disorders in this large family

Methods

Results

Conclusion