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A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy

Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, Hsp...

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Autores principales: Antona, Vincenzo, Scalia, Federica, Giorgio, Elisa, Radio, Francesca C., Brusco, Alfredo, Oliveri, Massimiliano, Corsello, Giovanni, Lo Celso, Fabrizio, Vadalà, Maria, Conway de Macario, Everly, Macario, Alberto J. L., Cappello, Francesco, Giuffrè, Mario
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589105/
https://www.ncbi.nlm.nih.gov/pubmed/33076433
http://dx.doi.org/10.3390/ijms21207631
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author Antona, Vincenzo
Scalia, Federica
Giorgio, Elisa
Radio, Francesca C.
Brusco, Alfredo
Oliveri, Massimiliano
Corsello, Giovanni
Lo Celso, Fabrizio
Vadalà, Maria
Conway de Macario, Everly
Macario, Alberto J. L.
Cappello, Francesco
Giuffrè, Mario
author_facet Antona, Vincenzo
Scalia, Federica
Giorgio, Elisa
Radio, Francesca C.
Brusco, Alfredo
Oliveri, Massimiliano
Corsello, Giovanni
Lo Celso, Fabrizio
Vadalà, Maria
Conway de Macario, Everly
Macario, Alberto J. L.
Cappello, Francesco
Giuffrè, Mario
author_sort Antona, Vincenzo
collection PubMed
description Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, Hsp60) and II (e.g., Chaperonin Containing T-Complex polypeptide 1, CCT). Examples of the former are hypomyelinating leukodystrophy 4 (HLD4 or MitCHAP60) and hereditary spastic paraplegia (SPG13). A distal sensory mutilating neuropathy has been linked to a mutation [p.(His147Arg)] in subunit 5 of the CCT5 gene. Here, we describe a new possibly pathogenic variant [p.(Leu224Val)] of the same subunit but with a different phenotype. This yet undescribed disease affects a girl with early onset demyelinating neuropathy and a severe motor disability. By whole exome sequencing (WES), we identified a homozygous CCT5 c.670C>G p.(Leu224Val) variant in the CCT5 gene. In silico 3D-structure analysis and bioinformatics indicated that this variant could undergo abnormal conformation and could be pathogenic. We compared the patient’s clinical, neurophysiological and laboratory data with those from patients carrying p.(His147Arg) in the equatorial domain. Our patient presented signs and symptoms absent in the p.(His147Arg) cases. Molecular dynamics simulation and modelling showed that the Leu224Val mutation that occurs in the CCT5 intermediate domain near the apical domain induces a conformational change in the latter. Noteworthy is the striking difference between the phenotypes putatively linked to mutations in the same CCT subunit but located in different structural domains, offering a unique opportunity for elucidating their distinctive roles in health and disease
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spelling pubmed-75891052020-10-29 A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy Antona, Vincenzo Scalia, Federica Giorgio, Elisa Radio, Francesca C. Brusco, Alfredo Oliveri, Massimiliano Corsello, Giovanni Lo Celso, Fabrizio Vadalà, Maria Conway de Macario, Everly Macario, Alberto J. L. Cappello, Francesco Giuffrè, Mario Int J Mol Sci Article Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, Hsp60) and II (e.g., Chaperonin Containing T-Complex polypeptide 1, CCT). Examples of the former are hypomyelinating leukodystrophy 4 (HLD4 or MitCHAP60) and hereditary spastic paraplegia (SPG13). A distal sensory mutilating neuropathy has been linked to a mutation [p.(His147Arg)] in subunit 5 of the CCT5 gene. Here, we describe a new possibly pathogenic variant [p.(Leu224Val)] of the same subunit but with a different phenotype. This yet undescribed disease affects a girl with early onset demyelinating neuropathy and a severe motor disability. By whole exome sequencing (WES), we identified a homozygous CCT5 c.670C>G p.(Leu224Val) variant in the CCT5 gene. In silico 3D-structure analysis and bioinformatics indicated that this variant could undergo abnormal conformation and could be pathogenic. We compared the patient’s clinical, neurophysiological and laboratory data with those from patients carrying p.(His147Arg) in the equatorial domain. Our patient presented signs and symptoms absent in the p.(His147Arg) cases. Molecular dynamics simulation and modelling showed that the Leu224Val mutation that occurs in the CCT5 intermediate domain near the apical domain induces a conformational change in the latter. Noteworthy is the striking difference between the phenotypes putatively linked to mutations in the same CCT subunit but located in different structural domains, offering a unique opportunity for elucidating their distinctive roles in health and disease MDPI 2020-10-15 /pmc/articles/PMC7589105/ /pubmed/33076433 http://dx.doi.org/10.3390/ijms21207631 Text en © 2020 by the authors. 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
Antona, Vincenzo
Scalia, Federica
Giorgio, Elisa
Radio, Francesca C.
Brusco, Alfredo
Oliveri, Massimiliano
Corsello, Giovanni
Lo Celso, Fabrizio
Vadalà, Maria
Conway de Macario, Everly
Macario, Alberto J. L.
Cappello, Francesco
Giuffrè, Mario
A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy
title A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy
title_full A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy
title_fullStr A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy
title_full_unstemmed A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy
title_short A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy
title_sort novel cct5 missense variant associated with early onset motor neuropathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589105/
https://www.ncbi.nlm.nih.gov/pubmed/33076433
http://dx.doi.org/10.3390/ijms21207631
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