Journal Article

Truncating mutations in RBM12 are associated with psychosis

Huttenlocher, Johanna, Haraldsson, Magnus, Suvisaari, Jaana, Gudmundsdottir, Steinunn, Norddahl, Gudmundur L, Thorgeirsson, Thorgeir E, Stefansson, Kari, Paunio, Tiina, Sveinbjornsson, Gardar, Torniainen-Holm, Minna, Arnarsdottir, Sunna, Ingimarsson, Oddur, Frigge, Michael L, Tyrfingsson, Thorarinn, Steinberg, Stacy, Gudbjartsson, Daniel F, Jonsdottir, Gudrun A, Sigurdsson, Engilbert, Stefansson, Hreinn, Kong, Augustine

2017

Overview

Kari Stefansson and colleagues identify a nonsense mutation in RBM12 segregating with psychosis in an extended Icelandic pedigree and an independent frameshift mutation in RBM12 segregating with psychosis in a Finnish family. They further show that carriers of the Icelandic mutation who are unaffected by psychosis exhibit a psychiatric disorder and cognitive test battery profile resembling that of patients with schizophrenia. Thus far, a handful of highly penetrant mutations conferring risk of psychosis have been discovered. Here we used whole-genome sequencing and long-range phasing to investigate an Icelandic kindred containing ten individuals with psychosis (schizophrenia, schizoaffective disorder or psychotic bipolar disorder). We found that all affected individuals carry RBM12 (RNA-binding-motif protein 12) c.2377G>T ( P = 2.2 × 10 −4 ), a nonsense mutation that results in the production of a truncated protein lacking a predicted RNA-recognition motif. We replicated the association in a Finnish family in which a second RBM12 truncating mutation (c.2532delT) segregates with psychosis ( P = 0.020). c.2377G>T is not fully penetrant for psychosis; however, we found that carriers unaffected by psychosis resemble patients with schizophrenia in their non-psychotic psychiatric disorder and neuropsychological test profile ( P = 0.0043) as well as in their life outcomes (including an increased chance of receiving disability benefits, P = 0.011). As RBM12 has not previously been linked to psychosis, this work provides new insight into psychiatric disease.

• Publisher: Springer New York,Nature Publishing Group
• Subject: 45/23 / 631/208 / 631/378 / 692/699/476/1799 / Agriculture / Animal Genetics and Genomics / Biomedicine / Bipolar disorder / Cancer Research / Codon, Nonsense / Family Health / Female / Gene Function / Gene mutation / Genetic aspects / Genome, Human / Human Genetics / Humans / Iceland / letter / Male / Mental disorders / Mutation / Nonsense mutation / Physiological aspects / Psychosis / Psychotic disorders / Psychotic Disorders - genetics / Ribonucleic acid / Risk factors / RNA / RNA-Binding Proteins - genetics / Schizoaffective disorder / Schizophrenia / Sequence Analysis, DNA / Siblings / Studies