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    A novel cct5 missense variant associated with early onset motor neuropathy

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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
    de Macario, Everly Conway
    Macario, Alberto J.L.
    Cappello, Francesco
    Giuffrè, Mario
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    Date
    2020-10-02
    Journal
    International Journal of Molecular Sciences
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3390/ijms21207631
    Abstract
    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 Ricerca
    Keyword
    CCT5
    Chaperoning system
    Chaperonins
    Genetic chaperonopathies
    Genetic variants
    Motor neuropathy
    Mutation
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13927
    ae974a485f413a2113503eed53cd6c53
    10.3390/ijms21207631
    Scopus Count
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