Editors' ChoiceNeuroscience

Finnish Bottlenecks Enrich Risk-Conferring Deletion of TOP3β

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Science Translational Medicine  18 Sep 2013:
Vol. 5, Issue 203, pp. 203ec156
DOI: 10.1126/scitranslmed.3007557

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA, and Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. E-mail: bneale{at}broadinstitute.org

The demographic history of Finland can be characterized by a series of population bottlenecks that have resulted in subsets of Finns with genomes that show considerably less genetic variation but at the same time have dramatically higher rates of specific deleterious mutations. As a consequence, such population isolates can reveal new genetic risk factors that are considerably rarer than in the general population. Furthermore, a population isolate increases the chance of homozygosity, which can further enhance the impact of such deleterious genetic variants. Stoll and colleagues demonstrate the value of studying such population isolates by mapping a deletion in the TOP3β gene in a sample of schizophrenic patients.

TOP3β encodes an RNA topoisomerase, an enzyme that alters the topology of RNA. Upon identification of the deletion in TOP3β, the authors conducted a series of experiments to determine the function of the gene product and biological impact of its absence. The schizophrenia-associated deletion within the TOP3β gene significantly reduced its expression; in a genome-wide gene expression analysis of samples from the Finnish schizophrenic patients, no other single gene displayed significant reduction in expression.

In human embryonic kidney 293 cells, the authors generated a FLAG/hemagluttinin–tagged TOP3β protein, enabling immunoprecipitation via a FLAG antibody. This led to the identification of protein-protein interactions with the fragile-X mental retardation protein (FMRP), which regulates translation of neuronal mRNAs, and Tudor domain–containing protein 3 (TDRD3), a transcriptional coactivator that binds to molecular marks on histone tails. The latter observation led the authors to hypothesize that TDRD3 is a bridging factor in a heterotrimeric TOP3β-TDRD3-FMRP (TTF) complex. As further validation, the authors also demonstrated that each of the components of the TTF complex is present in mouse neuronal tissue. Taken together, these experiments suggest that TOP3β plays a role in the metabolism of mRNAs bound to FMRP.

This finding is consistent with autism research (www.ncbi.nlm.nih.gov/pubmed/22542183), showing that genes whose products interact with FRMP are enriched for de novo loss-of-function mutations, which suggest that FMRP targets play a wider role in the development of normal cognitive functioning. Stoll and colleagues demonstrated that in addition to increased risk to schizophrenia, carriers of the TOP3β deletion also display higher levels of cognitive impairment compared with that in other patients with schizophrenia. Thus, the new work contributes to an evolving story that implicates the disruption of FMRP-interacting proteins in neuropsychiatric diseases with potential cognitive consequences.

G. Stoll et al., Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nat. Neurosci. 16, 1228–1237 (2013).[Abstract]

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