Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes.

Autor:	Button EL; Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia., Rossi JJ; Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia., McDougal DP; Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia., Bruning JB; Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.; Institute of Photonics and Advanced Sensing, School of Biological Sciences, University of Adelaide, Adelaide, Australia., Peet DJ; Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia., Bersten DC; Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, U.S.A.; Baylor Genetics Laboratories, Houston, TX, U.S.A., Whitelaw ML; Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.
Jazyk:	angličtina
Zdroj:	The Biochemical journal [Biochem J] 2022 Jul 15; Vol. 479 (13), pp. 1441-1454.
DOI:	10.1042/BCJ20220209
Abstrakt:	Single-minded 2 (SIM2) is a neuron-enriched basic Helix-Loop-Helix/PER-ARNT-SIM (bHLH/PAS) transcription factor essential for mammalian survival. SIM2 is located within the Down syndrome critical region (DSCR) of chromosome 21, and manipulation in mouse models suggests Sim2 may play a role in brain development and function. During the screening of a clinical exome sequencing database, nine SIM2 non-synonymous mutations were found which were subsequently investigated for impaired function using cell-based reporter gene assays. Many of these human variants attenuated abilities to activate transcription and were further characterized to determine the mechanisms underpinning their deficiencies. These included impaired partner protein dimerization, reduced DNA binding, and reduced expression and nuclear localization. This study highlighted several SIM2 variants found in patients with disabilities and validated a candidate set as potentially contributing to pathology. (© 2022 The Author(s).)
Databáze:	MEDLINE
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