A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy

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

Muscle Histopathological Abnormalities in a Patient With a CCT5 Mutation Predicted to Affect the Apical Domain of the Chaperonin Subunit

“…An illustrative example of neurochaperonopathy is the distal sensory mutilating neuropathy associated with a point mutation on the CCT5 subunit described earlier ( Bouhouche et al, 2006a ; Bouhouche et al, 2006b ). More recently, we reported a different genetic variant of CCT5 that was associated with a severe distal motor neuropathy ( Antona et al, 2020 ), which is the object of this article.…”

“…The scarcity of data on the histopathological manifestations of chaperonopathies impedes advances in the elucidation of the molecular mechanisms underpinning the severe muscular deficiency observed in patients and this, in turn, stands in the way for developing specific treatments. To remedy this lack of necessary knowledge, we studied the available muscle sample from the patient reported earlier, who suffered from a severe motor disorder and carried a point mutation on the CCT5 subunit ( Antona et al, 2020 ). Here, we define histological abnormalities occurring in striated skeletal muscle from this patient.…”

The Neurochaperonopathies: Anomalies of the Chaperone System with Pathogenic Effects in Neurodegenerative and Neuromuscular Disorders

“…For example, a missense mutation of the subunit number 5 of CCT, CCT5, was reported to be accompanied by a phenotype characterized mostly by distal sensory mutilating neuropathy [56,57]. In contrast, another recently discovered mutant located in a different structural domain of CCT5 was associated with a motor distal neuropathy without mutilation [58]. Thus, the impact of the mutation on the properties and functions of the chaperone molecule, and the accompanying tissue abnormalities and lesions observed in patients may greatly differ, depending on the location of the mutant amino acid, but other elements, e.g., environmental and nutritional factors that may also contribute to the generation of diverse phenotypes cannot be excluded.…”

“…More recently, a new disease was described associated with a different missense mutation, p.(Leu224Val), in CCT5 [58]. While the previously described mutation His147Arg caused a distal sensory neuropathy more pronounced in adulthood, the newly found mutation is associated with a motor neuropathy of early onset.…”

The TRiCky Business of Protein Folding in Health and Disease

“…The importance of the CCT5 subunit in preventing neurological disorders was further shown in a different case of early-onset demyelinating neuropathy in which a L224V mutation in the intermediate domain of CCT5 was described. Similar modeling of CCT5 L224V, with or without nucleotides, showed that the apical domain was the most changed, affecting the subunit’s conformation ( Antona et al, 2020 ). Aberrant expression of other CCT subunits, like CCT2, also correlated with Alzheimer’s disease or Parkinson’s disease and could be used as biomarkers to assist with neurological disease prognosis and management ( Brehme et al, 2014 ; Xie H. et al, 2016 ; Liu et al, 2020 ).…”