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To date, mutations in <jats:italic>PTCD3<\/jats:italic>, 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\u2013clonic seizures. Brain MRI showed optic nerve atrophy and thalamic changes, consistent with Leigh syndrome. WES and RNA\u2010seq identified compound heterozygous variants in <jats:italic>PTCD3<\/jats:italic> in both families: c.[1453\u20101G&gt;C];[1918C&gt;G] and c.[710del];[902C&gt;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\u2010resolution 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\u2010type <jats:italic>PTCD3<\/jats:italic> in immortalized fibroblasts restored the steady\u2010state 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 <jats:italic>PTCD3<\/jats:italic> mRNA processing. The fourth variant was a frameshift leading to a truncated protein. In summary, we provide evidence of <jats:italic>PTCD3<\/jats:italic> involvement in human disease confirming that PTCD3 deficiency is definitively associated with Leigh syndrome.<\/jats:p>","DOI":"10.1111\/bpa.13134","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T23:22:05Z","timestamp":1669850525000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Leigh syndrome is the main clinical characteristic of <scp>PTCD3<\/scp> deficiency"],"prefix":"10.1111","volume":"33","author":[{"given":"Gerard","family":"Mu\u00f1oz\u2010Pujol","sequence":"first","affiliation":[{"name":"Secci\u00f3 d'Errors Cong\u00e8nits del Metabolisme\u2010IBC, Servei de Bioqu\u00edmica i Gen\u00e8tica Molecular Hospital Cl\u00ednic de Barcelona, IDIBAPS, CIBERER  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan 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Technical University of Munich  Garching Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holger","family":"Prokisch","sequence":"additional","affiliation":[{"name":"School of Medicine Institute of Human Genetics, Technische Universit\u00e4t M\u00fcnchen  Munich Germany"},{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen  Neuherberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Artuch","sequence":"additional","affiliation":[{"name":"Clinical Biochemistry and Molecular Medicine and Genetics Departments Institut de Recerca Sant Joan de D\u00e9u, Hospital Sant Joan de D\u00e9u, and CIBERER  Esplugues de Llobregat Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonia","family":"Ribes","sequence":"additional","affiliation":[{"name":"Secci\u00f3 d'Errors Cong\u00e8nits del Metabolisme\u2010IBC, Servei de Bioqu\u00edmica i Gen\u00e8tica Molecular Hospital Cl\u00ednic de 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