Mutations of GEMIN5 are associated with coenzyme Q 10 deficiency: long-term follow-up after treatment.

Autor: Cascajo-Almenara MV; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain., Juliá-Palacios N; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., Urreizti R; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain.; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., Sánchez-Cuesta A; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain., Fernández-Ayala DM; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain., García-Díaz E; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, 41013, Sevilla, Spain., Oliva C; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., O Callaghan MDM; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., Paredes-Fuentes AJ; Division of Inborn Errors of Metabolism-IBC, Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, 08028, Barcelona, Spain., Moreno-Lozano PJ; Internal Medicine Department, Clinic Hospital and University of Barcelona, 08036, Barcelona, Spain., Muchart J; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., Nascimento A; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain.; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., Ortez CI; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., Natera-de Benito D; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., Pineda M; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., Rivera N; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., Fortuna TR; Department of Pediatrics, Childrens Hospital of Pittsburgh and Children's Neuroscience Institute, University of Pittsburgh Medical Center and Children's Hospital of Pittsburgh, 15224, Pittsburgh, PA, USA., Rajan DS; Department of Pediatrics, Childrens Hospital of Pittsburgh and Children's Neuroscience Institute, University of Pittsburgh Medical Center and Children's Hospital of Pittsburgh, 15224, Pittsburgh, PA, USA., Navas P; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, 41013, Sevilla, Spain., Salviati L; Clinical Genetics Unit, Department of Women and Children's Health, Padua University, 35128, Padua, Italy., Palau F; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain.; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain.; Division of Pediatrics, Faculty of Medicine and Health Sciences, University of Barcelona, 08036, Barcelona, Spain., Yubero D; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain.; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., García-Cazorla A; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain.; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain., Pandey UB; Department of Pediatrics, Childrens Hospital of Pittsburgh and Children's Neuroscience Institute, University of Pittsburgh Medical Center and Children's Hospital of Pittsburgh, 15224, Pittsburgh, PA, USA. udai@pitt.edu., Santos-Ocaña C; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain. csanoca@upo.es.; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, 41013, Sevilla, Spain. csanoca@upo.es., Artuch R; Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain. Rafael.artuch@sjd.es.; Institut de Recerca Sant Joan de Déu. Clinical Biochemistry, Paediatric Neurology, Radiology and Genetics Departments, 08950, Barcelona, Spain. Rafael.artuch@sjd.es.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Apr; Vol. 32 (4), pp. 426-434. Date of Electronic Publication: 2024 Feb 05.
DOI: 10.1038/s41431-023-01526-2
Abstrakt: GEMIN5 exerts key biological functions regulating pre-mRNAs intron removal to generate mature mRNAs. A series of patients were reported harboring mutations in GEMIN5. No treatments are currently available for this disease. We treated two of these patients with oral Coenzyme Q 10 (CoQ 10 ), which resulted in neurological improvements, although MRI abnormalities remained. Whole Exome Sequencing demonstrated compound heterozygosity at the GEMIN5 gene in both cases: Case one: p.Lys742* and p.Arg1016Cys; Case two: p.Arg1016Cys and p.Ser411Hisfs*6. Functional studies in fibroblasts revealed a decrease in CoQ 10 biosynthesis compared to controls. Supplementation with exogenous CoQ 10 restored it to control intracellular CoQ 10 levels. Mitochondrial function was compromised, as indicated by the decrease in oxygen consumption, restored by CoQ 10 supplementation. Transcriptomic analysis of GEMIN5 patients compared with controls showed general repression of genes involved in CoQ 10 biosynthesis. In the rigor mortis defective flies, CoQ 10 levels were decreased, and CoQ 10 supplementation led to an improvement in the adult climbing assay performance, a reduction in the number of motionless flies, and partial restoration of survival. Overall, we report the association between GEMIN5 dysfunction and CoQ 10 deficiency for the first time. This association opens the possibility of oral CoQ 10 therapy, which is safe and has no observed side effects after long-term therapy.
(© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)
Databáze: MEDLINE
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