ORCID Profile
0000-0002-8398-0862
Current Organisation
The University of Edinburgh
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Publisher: Oxford University Press (OUP)
Date: 28-01-2014
DOI: 10.1093/HMG/DDU025
Publisher: Cold Spring Harbor Laboratory
Date: 03-06-2019
DOI: 10.1101/657163
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 ) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging (DTI) and cellular studies to evaluate the consequences of the t(1 ) 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 in white matter integrity compared to familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) case derived 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 ) oligodendrocyte progenitors were significantly reduced compared to controls. Thus we provide evidence that the t(1 ) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2019
DOI: 10.1101/525683
Abstract: Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected in iduals and 8,364 controls of European ancestry. We focused on three phenotypic groups the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, in iduals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABA A receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among in iduals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2 , and GABRG2 for GGE and LGI1, TRIM3 , and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2019
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Mandy Johnstone.