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Sønderby, I. E., Van der Meer, D., Moreau, C., Kaufmann, T., Walters, G. B., Ellegaard, M., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N. B., Blangero, J., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Bülow, R., Bøen, R., Cahn, W. and 125 moreSønderby, I. E., Van der Meer, D., Moreau, C., Kaufmann, T., Walters, G. B., Ellegaard, M., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N. J., Bernard, M., Blackburn, N. B., Blangero, J., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Bülow, R., Bøen, R., Cahn, W., Calhoun, V. D., Caspers, S., Ching, C. R. K., Cichon, S., Ciufolini, S., Crespo-Facorro, B., Curran, J. E., Dale, A. M., Dalvie, S., Dazzan, P., De Geus, E. J. C., De Zubicaray, G. I., De Zwarte, S. M. C., Desrivieres, S., Doherty, J. L., Donohoe, G., Draganski, B., Ehrlich, S., Eising, E., Espeseth, T., Fejgin, K., Fisher, S. E., Fladby, T., Frei, O., Frouin, V., Fukunaga, M., Gareau, T., Ge, T., Glahn, D. C., Grabe, H. J., Groenewold, N. A., Gústafsson, Ó., Haavik, J., Haberg, A. K., Hall, J., Hashimoto, R., Hehir-Kwa, J. Y., Hibar, D. P., Hillegers, M. H. J., Hoffmann, P., Holleran, L., Holmes, A. J., Homuth, G., Hottenga, J.-J., Hulshoff Pol, H. E., Ikeda, M., Jahanshad, N., Jockwitz, C., Johansson, S., Jönsson, E. G., Jørgensen, N. R., Kikuchi, M., Knowles, E. E. M., Kumar, K., Le Hellard, S., Leu, C., Linden, D. E., Liu, J., Lundervold, A., Lundervold, A. J., Maillard, A. M., Martin, N. G., Martin-Brevet, S., Mather, K. A., Mathias, S. R., McMahon, K. L., McRae, A. F., Medland, S. E., Meyer-Lindenberg, A., Moberget, T., Modenato, C., Monereo Sánchez, J., Morris, D. W., Mühleisen, T. W., Murray, R. M., Nielsen, J., Nordvik, J. E., Nyberg, L., Olde Loohuis, L. M., Ophoff, R. A., Owen, M. J., Paus, T., Pausova, Z., Peralta, J. M., Pike, B., Prieto, C., Quinlan, E. B., Reinbold, C. S., Reis Marques, T., Rucker, J. J. H., Sachdev, P. S., Sando, S. B., Schofield, P. R., Schork, A. J., Schumann, G., Shin, J., Shumskaya, E., Silva, A. I., Sisodiya, S. M., Steen, V. M., Stein, D. J., Strike, L. T., Suzuki, I. K., Tamnes, C. K., Teumer, A., Thalamuthu, A., Tordesillas-Gutiérrez, D., Uhlmann, A., Úlfarsson, M. Ö., Van 't Ent, D., Van den Bree, M. B. M., Vanderhaeghen, P., Vassos, E., Wen, W., Wittfeld, K., Wright, M. J., Agartz, I., Djurovic, S., Westlye, L. T., Stefánsson, H., Stefánsson, K., Jacquemont, S., Thompson, P. M., Andreassen, O. A., & the ENIGMA-CNV working group (2021). 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans. Translational Psychiatry, 11: 182. doi:10.1038/s41398-021-01213-0.
Abstract
Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function. -
De Vries, B., Eising, E., Broos, L. A. M., Koelewijn, S. C., Todorov, B., Frants, R. R., Boer, J. M., Ferraro, M. D., Thoen, P. A. C., & Van Den Maagdenberg, A. (2014). RNA expression profiling in brains of familial hemiplegic migraine type 1 knock-in mice. Cephalalgia, 34(3), 174-182. doi:10.1177/0333102413502736.
Abstract
Background Various CACNA1A missense mutations cause familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of migraine with aura. FHM1 mutation R192Q is associated with pure hemiplegic migraine, whereas the S218L mutation causes hemiplegic migraine, cerebellar ataxia, seizures, and mild head trauma-induced brain edema. Transgenic knock-in (KI) migraine mouse models were generated that carried either the FHM1 R192Q or the S218L mutation and were shown to exhibit increased CaV2.1 channel activity. Here we investigated their cerebellar and caudal cortical transcriptome. Methods Caudal cortical and cerebellar RNA expression profiles from mutant and wild-type mice were studied using microarrays. Respective brain regions were selected based on their relevance to migraine aura and ataxia. Relevant expression changes were further investigated at RNA and protein level by quantitative polymerase chain reaction (qPCR) and/or immunohistochemistry, respectively. Results Expression differences in the cerebellum were most pronounced in S218L mice. Particularly, tyrosine hydroxylase, a marker of delayed cerebellar maturation, appeared strongly upregulated in S218L cerebella. In contrast, only minimal expression differences were observed in the caudal cortex of either mutant mice strain. Conclusion Despite pronounced consequences of migraine gene mutations at the neurobiological level, changes in cortical RNA expression in FHM1 migraine mice compared to wild-type are modest. In contrast, pronounced RNA expression changes are seen in the cerebellum of S218L mice and may explain their cerebellar ataxia phenotype
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