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Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel MBOAT7 Variant in Patients With Intellectual Disability

The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) gene is associated with intellectual disability, early onset seizures, and autism spectrum disorders. This study aimed to determine the pathogenetic mechanism of the MBOAT7 missense variant via molecular modeling. Three patients from...

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Autores principales: Lee, Jiwon, Shamim, Amen, Park, Jongho, Jang, Ja-Hyun, Kim, Ji Hye, Kwon, Jeong-Yi, Kim, Jong-Won, Kim, Kyeong Kyu, Lee, Jeehun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9058081/
https://www.ncbi.nlm.nih.gov/pubmed/35509994
http://dx.doi.org/10.3389/fneur.2022.836954
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author Lee, Jiwon
Shamim, Amen
Park, Jongho
Jang, Ja-Hyun
Kim, Ji Hye
Kwon, Jeong-Yi
Kim, Jong-Won
Kim, Kyeong Kyu
Lee, Jeehun
author_facet Lee, Jiwon
Shamim, Amen
Park, Jongho
Jang, Ja-Hyun
Kim, Ji Hye
Kwon, Jeong-Yi
Kim, Jong-Won
Kim, Kyeong Kyu
Lee, Jeehun
author_sort Lee, Jiwon
collection PubMed
description The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) gene is associated with intellectual disability, early onset seizures, and autism spectrum disorders. This study aimed to determine the pathogenetic mechanism of the MBOAT7 missense variant via molecular modeling. Three patients from a consanguineous family were found to have a homozygous c.757G>A (p.Glu253Lys) variant of MBOAT7. The patients showed prominent dysfunction in gait, swallowing, vocalization, and fine motor function and had intellectual disabilities. Brain magnetic resonance imaging showed signal changes in the bilateral globus pallidi and cerebellar dentate nucleus, which differed with age. In the molecular model of human MBOAT7, Glu253 in the wild-type protein is located close to the backbone carbonyl oxygens in the loop near the helix, suggesting that the ionic interaction could contribute to the conformational stability of the funnel. Molecular modeling showed that Lys253 in the mutant protein was expected to alter the surface charge distribution, thereby potentially affecting substrate specificity. Changes in conformational stability and substrate specificity through varied ionic interactions are the suggested pathophysiological mechanisms of the MBOAT7 variant found in patients with intellectual disabilities.
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spelling pubmed-90580812022-05-03 Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel MBOAT7 Variant in Patients With Intellectual Disability Lee, Jiwon Shamim, Amen Park, Jongho Jang, Ja-Hyun Kim, Ji Hye Kwon, Jeong-Yi Kim, Jong-Won Kim, Kyeong Kyu Lee, Jeehun Front Neurol Neurology The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) gene is associated with intellectual disability, early onset seizures, and autism spectrum disorders. This study aimed to determine the pathogenetic mechanism of the MBOAT7 missense variant via molecular modeling. Three patients from a consanguineous family were found to have a homozygous c.757G>A (p.Glu253Lys) variant of MBOAT7. The patients showed prominent dysfunction in gait, swallowing, vocalization, and fine motor function and had intellectual disabilities. Brain magnetic resonance imaging showed signal changes in the bilateral globus pallidi and cerebellar dentate nucleus, which differed with age. In the molecular model of human MBOAT7, Glu253 in the wild-type protein is located close to the backbone carbonyl oxygens in the loop near the helix, suggesting that the ionic interaction could contribute to the conformational stability of the funnel. Molecular modeling showed that Lys253 in the mutant protein was expected to alter the surface charge distribution, thereby potentially affecting substrate specificity. Changes in conformational stability and substrate specificity through varied ionic interactions are the suggested pathophysiological mechanisms of the MBOAT7 variant found in patients with intellectual disabilities. Frontiers Media S.A. 2022-04-18 /pmc/articles/PMC9058081/ /pubmed/35509994 http://dx.doi.org/10.3389/fneur.2022.836954 Text en Copyright © 2022 Lee, Shamim, Park, Jang, Kim, Kwon, Kim, Kim and Lee. 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 Neurology
Lee, Jiwon
Shamim, Amen
Park, Jongho
Jang, Ja-Hyun
Kim, Ji Hye
Kwon, Jeong-Yi
Kim, Jong-Won
Kim, Kyeong Kyu
Lee, Jeehun
Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel MBOAT7 Variant in Patients With Intellectual Disability
title Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel MBOAT7 Variant in Patients With Intellectual Disability
title_full Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel MBOAT7 Variant in Patients With Intellectual Disability
title_fullStr Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel MBOAT7 Variant in Patients With Intellectual Disability
title_full_unstemmed Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel MBOAT7 Variant in Patients With Intellectual Disability
title_short Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel MBOAT7 Variant in Patients With Intellectual Disability
title_sort functional and structural changes in the membrane-bound o-acyltransferase family member 7 (mboat7) protein: the pathomechanism of a novel mboat7 variant in patients with intellectual disability
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9058081/
https://www.ncbi.nlm.nih.gov/pubmed/35509994
http://dx.doi.org/10.3389/fneur.2022.836954
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