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.

Keywords: CCT5; chaperoning system; chaperonins; genetic chaperonopathies; genetic variants; motor neuropathy; mutation.

Figure 1

Pedigree (A) and genetic analyses (B). Whole exome sequencing identified a homozygous missense variant in exon 5 of CCT5 c.670C>G p.(Leu224Val) (NM_012073). Leucine 224 is evolutionarily conserved from yeasts to vertebrates (C), each color corresponds to a single specific amino acid.

Figure 2

Proband at seven years of age showing microcephaly without evident dysmorphic features (A,B), tetra paresis and severe hypotonia (C).

Figure 3

Protein conformational status for wild type and mutant CCT5 proteins. Image (A) is the superposition of the most probable conformations obtained from the molecular dynamics simulation of wild type CCT5 without nucleotide (gold), or bound to ATP (lilac), or bound to ADP (cyan). The image shows that the protein takes different conformations in the three conditions, especially at the level of the apical domain. Image (B) is the superposition of the most probable conformations obtained from the molecular dynamics simulation of mutant Leu224Val CCT5 without nucleotide (gold), or bound to ATP (lilac), or bound to ADP (cyan). The image shows that the mutant protein takes different conformations as compared with the wild type in the three conditions examined, especially at the level of the apical domain.