Abstract 963: IDH2(R140Q) knock-in mouse recapitulating human type II D-2-hydroxyglutaric aciduria

Abstract

Abstract A single amino acid substitution, R140Q, in isocitrate dehydrogenase 2 (IDH2) confers a novel enzymatic activity that converts α-ketoglutarate (αKG) to D-2-hydroxyglutarate (D-2-HG). This gain-of-function mutation has been identified in patients with type II D-2-hydroxyglutaric aciduria (D-2-HGA), a rare and severe neurometabolic disorder that presents with a range of clinical findings, including seizures, hypotonia, developmental delay, cardiomyopathy, dysmorphic features and early death. There are no effective therapies for this inherited autosomal dominant disease. Here, we report the generation and characterization of a mouse genetic model that recapitulates key features of type II D-2-HGA. A single amino acid replacement, R140Q, was introduced via homologous recombination into the endogenous mouse IDH2 gene locus, to create heterozygous IDH2(R140Q) knock-in (KI) mice. These KI mice produce significantly elevated levels of D-2-HG in all tissues tested, and exhibit multiple defects consistent with symptoms from D-2-HGA patients, including early mortality, brain lesions, and cardiac hypertrophy. Echocardiogram reveals impaired systolic function with a diffusely hypokinetic left ventricle and low ejection fraction. The IDH2(R140Q) knock-in mouse model provides a valuable tool to elucidate the underlying disease mechanism of D-2-HGA and to evaluate ways to mitigate the disease. Citation Format: Fang Wang, Jeremy Travins, Zhizhong Lin, Lee Silverman, Yue Chen, Yuxuan Lu, Hua Yang, Michael Su, Yong Cang, Kate Ellwood-Yen, Shengfang Jin. IDH2(R140Q) knock-in mouse recapitulating human type II D-2-hydroxyglutaric aciduria. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 963. doi:10.1158/1538-7445.AM2014-963