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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
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.
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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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