Open AccessCharacterization of functionally deficient SIM2 variants found in patients with neurological phenotypes
Author(s) -
Emily L. Button,
Joseph J. Rossi,
Daniel P. McDougal,
John B. Bruning,
Daniel J. Peet,
David C. Bersten,
Jill A. Rosenfeld,
Murray L. Whitelaw
Publication year - 2022
Publication title -
biochemical journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.706
H-Index - 265
eISSN - 1470-8728
pISSN - 0264-6021
DOI - 10.1042/bcj20220209
Subject(s) - transcription factor , phenotype , biology , aryl hydrocarbon receptor nuclear translocator , genetics , exome sequencing , gene , transcription (linguistics) , function (biology) , microbiology and biotechnology , computational biology , linguistics , philosophy , aryl hydrocarbon receptor
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.
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