Leigh syndrome is the main clinical characteristic of PTCD3 deficiency
Por:
Muñoz-Pujol G, Ortigoza-Escobar JD, Paredes-Fuentes AJ, Jou-Munoz C, Ugarteburu O, Gort L, Yubero-Siles D, Garcia-Cazorla A, O'Callaghan-Gordo M, Campistol-Plana J, Muchart-Lopez J, Yépez VA, Gusic M, Gagneur J, Prokisch H, Artuch-Iriberri R, Ribes A, Urreizti R and Tort F
Publicada:
1 may 2023
Ahead of Print:
30 nov 2022
Resumen:
Mitochondrial translation defects are a continuously growing group of disorders showing a large variety of clinical symptoms including a wide range of neurological abnormalities. To date, mutations in PTCD3, encoding a component of the mitochondrial ribosome, have only been reported in a single individual with clinical evidence of Leigh syndrome. Here, we describe three additional PTCD3 individuals from two unrelated families, broadening the genetic and phenotypic spectrum of this disorder, and provide definitive evidence that PTCD3 deficiency is associated with Leigh syndrome. The patients presented in the first months of life with psychomotor delay, respiratory insufficiency and feeding difficulties. The neurologic phenotype included dystonia, optic atrophy, nystagmus and tonic-clonic seizures. Brain MRI showed optic nerve atrophy and thalamic changes, consistent with Leigh syndrome. WES and RNA-seq identified compound heterozygous variants in PTCD3 in both families: c.[1453-1G>C];[1918C>G] and c.[710del];[902C>T]. The functional consequences of the identified variants were determined by a comprehensive characterization of the mitochondrial function. PTCD3 protein levels were significantly reduced in patient fibroblasts and, consistent with a mitochondrial translation defect, a severe reduction in the steady state levels of complexes I and IV subunits was detected. Accordingly, the activity of these complexes was also low, and high-resolution respirometry showed a significant decrease in the mitochondrial respiratory capacity. Functional complementation studies demonstrated the pathogenic effect of the identified variants since the expression of wild-type PTCD3 in immortalized fibroblasts restored the steady-state levels of complexes I and IV subunits as well as the mitochondrial respiratory capacity. Additionally, minigene assays demonstrated that three of the identified variants were pathogenic by altering PTCD3 mRNA processing. The fourth variant was a frameshift leading to a truncated protein. In summary, we provide evidence of PTCD3 involvement in human disease confirming that PTCD3 deficiency is definitively associated with Leigh syndrome.
Filiaciones:
Muñoz-Pujol G:
Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, Barcelona, Spain
Ortigoza-Escobar JD:
Pediatric Neurology Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
:
Clinical Biochemistry and Molecular Medicine and Genetics Departments, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, and CIBERER, Esplúgues de Llobregat, Barcelona, Spain
Jou-Munoz C:
Pathology Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, University of Barcelona, CIBERER, Esplugues de Llobregat, Barcelona, Spain
Ugarteburu O:
Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, Barcelona, Spain
Gort L:
Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, Barcelona, Spain
Yubero-Siles D:
Clinical Biochemistry and Molecular Medicine and Genetics Departments, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, and CIBERER, Esplúgues de Llobregat, Barcelona, Spain
Garcia-Cazorla A:
Pediatric Neurology Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
O'Callaghan-Gordo M:
Pediatric Neurology Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Campistol-Plana J:
Pediatric Neurology Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Muchart-Lopez J:
Pediatric Radiology Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Yépez VA:
School of Medicine, Institute of Human Genetics, Technische Universität München, Munich, Germany
Department of Informatics, Technical University of Munich, Garching, Germany
Gusic M:
School of Medicine, Institute of Human Genetics, Technische Universität München, Munich, Germany
Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany
Gagneur J:
School of Medicine, Institute of Human Genetics, Technische Universität München, Munich, Germany
Department of Informatics, Technical University of Munich, Garching, Germany
Prokisch H:
School of Medicine, Institute of Human Genetics, Technische Universität München, Munich, Germany
Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany
Artuch-Iriberri R:
Clinical Biochemistry and Molecular Medicine and Genetics Departments, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, and CIBERER, Esplúgues de Llobregat, Barcelona, Spain
Ribes A:
Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, Barcelona, Spain
Urreizti R:
Clinical Biochemistry and Molecular Medicine and Genetics Departments, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, and CIBERER, Esplúgues de Llobregat, Barcelona, Spain
Tort F:
Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, Barcelona, Spain
Seccio d'Errors Congenits del Metabolisme-IBC, Servei de Bioquimica i Genetica Molecular, Hospital Clinic de Barcelona, IDIBAPS, CIBERER, Barcelona, Spain.; Pediatric Neurology Department, Hospital Sant Joan de Deu, Esplugues de Llobregat, Barcelona, Spain.; Clinical Biochemistry and Molecular Medicine and Genetics Departments, Institut de Recerca Sant Joan de Deu, Hospital Sant Joan de Deu, and CIBERER, Esplugues de Llobregat, Barcelona, Spain.; Pathology Department, Institut de Recerca Sant Jo
Green Submitted, gold
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