A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy

International Journal of Molecular Sciences

Federica Scalia¹  Francesco Cappello¹  Maria Vadal๠ AlbertoJ. L. Macario²  Mario Giuffrè³  Giovanni Corsello³  Vincenzo Antona³  Elisa Giorgio⁴  Alfredo Brusco⁴  Everly Conway de Macario⁵  Fabrizio Lo Celso⁶  Massimiliano Oliveri⁷  FrancescaC. Radio⁸ 

[1] Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy;Department of Biomolecular Strategies, Genetics and Advanced Therapies, Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy;Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy;Department of Medical Sciences, University of Torino, 10126 Torino, Italy;Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA;Department of Physics and Chemistry—Emilio Segrè, University of Palermo, 90128 Palermo, Italy;Department of Psychological, Pedagogical and Educational Sciences, University of Palermo, 90128 Palermo, Italy;Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCSS, 00146 Rome, Italy;

关键词: CCT5;    chaperonins;    chaperoning system;    genetic variants;    mutation;    genetic chaperonopathies;   

DOI  :  10.3390/ijms21207631

来源: DOAJ

【 摘 要 】

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

【 授权许可】

Unknown