TY - JOUR
T1 - A novel cct5 missense variant associated with early onset motor neuropathy
AU - Antona, Vincenzo
AU - Scalia, Federica
AU - Giorgio, Elisa
AU - Radio, Francesca C.
AU - Brusco, Alfredo
AU - Oliveri, Massimiliano
AU - Corsello, Giovanni
AU - Lo Celso, Fabrizio
AU - Vadalà, Maria
AU - de Macario, Everly Conway
AU - Macario, Alberto J.L.
AU - Cappello, Francesco
AU - Giuffrè, Mario
N1 - Funding Information:
Funding: F.C. and F.S. were partially supported by the Department BIND of the University of Palermo, Palermo, Italy, and by the Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy. V.A., G.C. and M.G. were partially supported by the Department PROMISE of the University of Palermo, Palermo, Italy. A.J.L.M. and E.C.d.M. were partially supported by the Institute of Marine and Environmental Technology (IMET), Baltimore, MD, USA; this is IMET contribution number IMET 20-020. This research received funding specifically appointed to Department of Medical Sciences from the Italian Ministry for Education, University and Research (Ministero dell’Istruzione, dell’Università e della Ricerca—MIUR) under the programme “Dipartimenti di Eccellenza 2018–2022” Project code D15D18000410001. The whole exome sequencing was performed as part of the Autism Sequencing Consortium and was supported by the NIMH (MH111661). Part of this work was supported by the Italian National Operational Programme for Research and Competitiveness grant awarded to the project titled “Cyber Brain—Polo di innovazione” (Project code: PONa3_00210, European Regional Development Fund).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/10/2
Y1 - 2020/10/2
N2 - 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.
AB - 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.
KW - CCT5
KW - Chaperoning system
KW - Chaperonins
KW - Genetic chaperonopathies
KW - Genetic variants
KW - Motor neuropathy
KW - Mutation
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UR - http://www.scopus.com/inward/citedby.url?scp=85092901086&partnerID=8YFLogxK
U2 - 10.3390/ijms21207631
DO - 10.3390/ijms21207631
M3 - Article
C2 - 33076433
AN - SCOPUS:85092901086
VL - 21
SP - 1
EP - 12
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 20
M1 - 7631
ER -