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Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes
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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9342896/ https://www.ncbi.nlm.nih.gov/pubmed/35730699 http://dx.doi.org/10.1042/BCJ20220209 |
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author | Button, Emily L. Rossi, Joseph J. McDougal, Daniel P. Bruning, John B. Peet, Daniel J. Bersten, David C. Rosenfeld, Jill A. Whitelaw, Murray L. |
author_facet | Button, Emily L. Rossi, Joseph J. McDougal, Daniel P. Bruning, John B. Peet, Daniel J. Bersten, David C. Rosenfeld, Jill A. Whitelaw, Murray L. |
author_sort | Button, Emily L. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9342896 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93428962022-08-09 Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes Button, Emily L. Rossi, Joseph J. McDougal, Daniel P. Bruning, John B. Peet, Daniel J. Bersten, David C. Rosenfeld, Jill A. Whitelaw, Murray L. Biochem J Mutation 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. Portland Press Ltd. 2022-07-13 /pmc/articles/PMC9342896/ /pubmed/35730699 http://dx.doi.org/10.1042/BCJ20220209 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Mutation Button, Emily L. Rossi, Joseph J. McDougal, Daniel P. Bruning, John B. Peet, Daniel J. Bersten, David C. Rosenfeld, Jill A. Whitelaw, Murray L. Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes |
title | Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes |
title_full | Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes |
title_fullStr | Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes |
title_full_unstemmed | Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes |
title_short | Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes |
title_sort | characterization of functionally deficient sim2 variants found in patients with neurological phenotypes |
topic | Mutation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9342896/ https://www.ncbi.nlm.nih.gov/pubmed/35730699 http://dx.doi.org/10.1042/BCJ20220209 |
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