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Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors

Different pathogenic variants in the same protein or even within the same domain of a protein may differ in their patterns of disease inheritance, with some of the variants behaving as negative dominant and others as autosomal recessive mutations. Here is presented a structural analysis and comparis...

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Autor principal: Bellacchio, Emanuele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730044/
https://www.ncbi.nlm.nih.gov/pubmed/33260935
http://dx.doi.org/10.3390/ijms21239016
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author Bellacchio, Emanuele
author_facet Bellacchio, Emanuele
author_sort Bellacchio, Emanuele
collection PubMed
description Different pathogenic variants in the same protein or even within the same domain of a protein may differ in their patterns of disease inheritance, with some of the variants behaving as negative dominant and others as autosomal recessive mutations. Here is presented a structural analysis and comparison of the molecular characteristics of the sites in fibrinogen γ-module, a fibrinogen component critical in multimerization processes, targeted by pathogenic variants (HGMD database) and by variants found in the healthy population (gnomAD database). The main result of this study is the identification of the molecular pathogenic mechanisms defining which pattern of disease inheritance is selected by mutations at the crossroad of autosomal recessive and negative dominant modalities. The observations in this analysis also warn about the possibility that several variants reported in the non-pathogenic gnomAD database might indeed be a hidden source of diseases with autosomal recessive inheritance or requiring a combination with other disease-causing mutations. Disease presentation might remain mostly unrevealed simply because the very low variant frequency rarely results in biallelic pathogenic mutations or the coupling with mutations in other genes contributing to the same disease. The results here presented provide hints for a deeper search of pathogenic mechanisms and modalities of disease inheritance for protein mutants participating in multimerization phenomena.
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spelling pubmed-77300442020-12-12 Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors Bellacchio, Emanuele Int J Mol Sci Article Different pathogenic variants in the same protein or even within the same domain of a protein may differ in their patterns of disease inheritance, with some of the variants behaving as negative dominant and others as autosomal recessive mutations. Here is presented a structural analysis and comparison of the molecular characteristics of the sites in fibrinogen γ-module, a fibrinogen component critical in multimerization processes, targeted by pathogenic variants (HGMD database) and by variants found in the healthy population (gnomAD database). The main result of this study is the identification of the molecular pathogenic mechanisms defining which pattern of disease inheritance is selected by mutations at the crossroad of autosomal recessive and negative dominant modalities. The observations in this analysis also warn about the possibility that several variants reported in the non-pathogenic gnomAD database might indeed be a hidden source of diseases with autosomal recessive inheritance or requiring a combination with other disease-causing mutations. Disease presentation might remain mostly unrevealed simply because the very low variant frequency rarely results in biallelic pathogenic mutations or the coupling with mutations in other genes contributing to the same disease. The results here presented provide hints for a deeper search of pathogenic mechanisms and modalities of disease inheritance for protein mutants participating in multimerization phenomena. MDPI 2020-11-27 /pmc/articles/PMC7730044/ /pubmed/33260935 http://dx.doi.org/10.3390/ijms21239016 Text en © 2020 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bellacchio, Emanuele
Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors
title Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors
title_full Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors
title_fullStr Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors
title_full_unstemmed Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors
title_short Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors
title_sort mutations causing mild or no structural damage in interfaces of multimerization of the fibrinogen γ-module more likely confer negative dominant behaviors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730044/
https://www.ncbi.nlm.nih.gov/pubmed/33260935
http://dx.doi.org/10.3390/ijms21239016
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