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Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects
Laterality defects (LDs) or asymmetrically positioned organs are a group of rare developmental disorders caused by environmental and/or genetic factors. However, the exact molecular pathophysiology of LD is not yet fully characterised. In this context, studying Arab population presents an ideal oppo...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473696/ https://www.ncbi.nlm.nih.gov/pubmed/34589502 http://dx.doi.org/10.3389/fmed.2021.724826 |
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author | Alsafwani, Rabab Said Nasser, Khalidah K. Shinawi, Thoraia Banaganapalli, Babajan ElSokary, Hanan Abdelhalim Zaher, Zhaher F. Shaik, Noor Ahmad Abdelmohsen, Gaser Al-Aama, Jumana Yousuf Shapiro, Adam J. O. Al-Radi, Osman Elango, Ramu Alahmadi, Turki |
author_facet | Alsafwani, Rabab Said Nasser, Khalidah K. Shinawi, Thoraia Banaganapalli, Babajan ElSokary, Hanan Abdelhalim Zaher, Zhaher F. Shaik, Noor Ahmad Abdelmohsen, Gaser Al-Aama, Jumana Yousuf Shapiro, Adam J. O. Al-Radi, Osman Elango, Ramu Alahmadi, Turki |
author_sort | Alsafwani, Rabab Said |
collection | PubMed |
description | Laterality defects (LDs) or asymmetrically positioned organs are a group of rare developmental disorders caused by environmental and/or genetic factors. However, the exact molecular pathophysiology of LD is not yet fully characterised. In this context, studying Arab population presents an ideal opportunity to discover the novel molecular basis of diseases owing to the high rate of consanguinity and genetic disorders. Therefore, in the present study, we studied the molecular basis of LD in Arab patients, using next-generation sequencing method. We discovered an extremely rare novel missense variant in MYO1D gene (Pro765Ser) presenting with visceral heterotaxy and left isomerism with polysplenia syndrome. The proband in this index family has inherited this homozygous variant from her heterozygous parents following the autosomal recessive pattern. This is the first report to show MYO1D genetic variant causing left–right axis defects in humans, besides previous known evidence from zebrafish, frog and Drosophila models. Moreover, our multilevel bioinformatics-based structural (protein variant structural modelling, divergence, and stability) analysis has suggested that Ser765 causes minor structural drifts and stability changes, potentially affecting the biophysical and functional properties of MYO1D protein like calmodulin binding and microfilament motor activities. Functional bioinformatics analysis has shown that MYO1D is ubiquitously expressed across several human tissues and is reported to induce severe phenotypes in knockout mouse models. In conclusion, our findings show the expanded genetic spectrum of LD, which could potentially pave way for the novel drug target identification and development of personalised medicine for high-risk families. |
format | Online Article Text |
id | pubmed-8473696 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84736962021-09-28 Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects Alsafwani, Rabab Said Nasser, Khalidah K. Shinawi, Thoraia Banaganapalli, Babajan ElSokary, Hanan Abdelhalim Zaher, Zhaher F. Shaik, Noor Ahmad Abdelmohsen, Gaser Al-Aama, Jumana Yousuf Shapiro, Adam J. O. Al-Radi, Osman Elango, Ramu Alahmadi, Turki Front Med (Lausanne) Medicine Laterality defects (LDs) or asymmetrically positioned organs are a group of rare developmental disorders caused by environmental and/or genetic factors. However, the exact molecular pathophysiology of LD is not yet fully characterised. In this context, studying Arab population presents an ideal opportunity to discover the novel molecular basis of diseases owing to the high rate of consanguinity and genetic disorders. Therefore, in the present study, we studied the molecular basis of LD in Arab patients, using next-generation sequencing method. We discovered an extremely rare novel missense variant in MYO1D gene (Pro765Ser) presenting with visceral heterotaxy and left isomerism with polysplenia syndrome. The proband in this index family has inherited this homozygous variant from her heterozygous parents following the autosomal recessive pattern. This is the first report to show MYO1D genetic variant causing left–right axis defects in humans, besides previous known evidence from zebrafish, frog and Drosophila models. Moreover, our multilevel bioinformatics-based structural (protein variant structural modelling, divergence, and stability) analysis has suggested that Ser765 causes minor structural drifts and stability changes, potentially affecting the biophysical and functional properties of MYO1D protein like calmodulin binding and microfilament motor activities. Functional bioinformatics analysis has shown that MYO1D is ubiquitously expressed across several human tissues and is reported to induce severe phenotypes in knockout mouse models. In conclusion, our findings show the expanded genetic spectrum of LD, which could potentially pave way for the novel drug target identification and development of personalised medicine for high-risk families. Frontiers Media S.A. 2021-09-13 /pmc/articles/PMC8473696/ /pubmed/34589502 http://dx.doi.org/10.3389/fmed.2021.724826 Text en Copyright © 2021 Alsafwani, Nasser, Shinawi, Banaganapalli, ElSokary, Zaher, Shaik, Abdelmohsen, Al-Aama, Shapiro, O. Al-Radi, Elango and Alahmadi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Medicine Alsafwani, Rabab Said Nasser, Khalidah K. Shinawi, Thoraia Banaganapalli, Babajan ElSokary, Hanan Abdelhalim Zaher, Zhaher F. Shaik, Noor Ahmad Abdelmohsen, Gaser Al-Aama, Jumana Yousuf Shapiro, Adam J. O. Al-Radi, Osman Elango, Ramu Alahmadi, Turki Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects |
title | Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects |
title_full | Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects |
title_fullStr | Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects |
title_full_unstemmed | Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects |
title_short | Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects |
title_sort | novel myo1d missense variant identified through whole exome sequencing and computational biology analysis expands the spectrum of causal genes of laterality defects |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473696/ https://www.ncbi.nlm.nih.gov/pubmed/34589502 http://dx.doi.org/10.3389/fmed.2021.724826 |
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