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A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy
- Source :
- International Journal of Molecular Sciences, International Journal of Molecular Sciences, Vol 21, Iss 7631, p 7631 (2020), Volume 21, Issue 20
- Publication Year :
- 2020
- Publisher :
- MDPI, 2020.
-
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&gt<br />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&rsquo<br />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
- Subjects :
- Mutation
Hereditary spastic paraplegia
Protein subunit
chaperoning system
Mutation, Missense
Biology
Molecular Dynamics Simulation
medicine.disease_cause
Catalysis
Article
Chaperonin
Inorganic Chemistry
lcsh:Chemistry
Heat shock protein
medicine
Missense mutation
Humans
Physical and Theoretical Chemistry
motor neuropathy
Age of Onset
Genetic variant
Molecular Biology
Gene
lcsh:QH301-705.5
Spectroscopy
Exome sequencing
Myelin Sheath
Genetic chaperonopathie
Genetics
genetic variants
Organic Chemistry
Infant, Newborn
General Medicine
medicine.disease
Phenotype
Computer Science Applications
CCT5
chaperonins
genetic chaperonopathies
mutation
lcsh:Biology (General)
lcsh:QD1-999
Female
Hereditary Sensory and Motor Neuropathy
Chaperonin Containing TCP-1
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 21
- Issue :
- 20
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....5d1dc7dc014199835c6315e63b48cbcd