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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...

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Autores principales: Button, Emily L., Rossi, Joseph J., McDougal, Daniel P., Bruning, John B., Peet, Daniel J., Bersten, David C., Rosenfeld, Jill A., Whitelaw, Murray L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2022
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.
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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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