A novel cct5 missense variant associated with early onset motor neuropathy
Author
Antona, VincenzoScalia, Federica
Giorgio, Elisa
Radio, Francesca C.
Brusco, Alfredo
Oliveri, Massimiliano
Corsello, Giovanni
Lo Celso, Fabrizio
Vadalà, Maria
de Macario, Everly Conway
Macario, Alberto J.L.
Cappello, Francesco
Giuffrè, Mario
Date
2020-10-02Journal
International Journal of Molecular SciencesPublisher
MDPI AGType
Article
Metadata
Show full item recordAbstract
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.Sponsors
Ministero dell’Istruzione, dell’Università e della RicercaKeyword
CCT5Chaperoning system
Chaperonins
Genetic chaperonopathies
Genetic variants
Motor neuropathy
Mutation
Identifier to cite or link to this item
http://hdl.handle.net/10713/13927ae974a485f413a2113503eed53cd6c53
10.3390/ijms21207631