{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:26:56Z","timestamp":1775802416595,"version":"3.50.1"},"reference-count":17,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T00:00:00Z","timestamp":1677024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shanghai Municipal Science and Technology Major Project","award":["2017SHZDZX01"],"award-info":[{"award-number":["2017SHZDZX01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Defect of GTPBP3, the human mitochondrial tRNA-modifying enzyme, can lead to Combined Oxidative Phosphorylation Deficiency 23 (COXPD23). Up to now, about 20 different variants of the GTPBP3 gene have been reported; however, genotype\u2013phenotype analysis has rarely been described. Here, we reported a 9-year-old boy with COXPD23 who presented with hyperlactatemia, hypertrophic cardiomyopathy, seizures, feeding difficulties, intellectual disability and motor developmental delay, and abnormal visual development. Biallelic pathogenic variants of the GTPBP3 gene were identified in this boy, one novel variant c.1102dupC (p. Arg368Profs*22) inherited from the mother and the other known variant c.689A&gt;C (p. Gln230Pro) inherited from father. We curated 18 COXPD23 patients with GTPBP3 variants to investigate the genotype\u2013phenotype correlation. We found that hyperlactatemia and cardiomyopathy were critical clinical features in COXPD23 and the average onset age was 1.7 years (3 months of age for the homozygote). Clinical classification of COXPD23 for the two types, severe and mild, was well described in this study. We observed arrhythmia and congestive heart failure frequently in the severe type with early childhood mortality, while developmental delay was mainly observed in the mild type. The proportion of homozygous variants (71.4%) significantly differed from that of compound heterozygous variants (18.1%) in the severe type. Compared with the variants in gnomAD, the proportion of LOFVs in GTPBP3 was higher in COXPD23 patients (48.6% versus 8.9%, p &lt; 0.0001 ****), and 31% of them were frameshift variants, showing the LOF mechanism of GTPBP3. Additionally, the variants in patients were significantly enriched in the TrmE-type G domain, indicating that the G domain was crucial for GTPBP3 protein function. The TrmE-type G domain contained several significant motifs involved in the binding of guanine nucleotides and Mg2+, the hydrolysis of GTP, and the regulation of the functional status of GTPases. In conclusion, we reported a mild COXPD23 case with typical GTPBP3-related symptoms, including seizures and abnormal visual development seldom observed previously. Our study provides novel insight into understanding the clinical diagnosis and genetic counseling of patients with COXPD23 by exploring the genetic pathogenesis and genotype\u2013phenotype correlation of COXPD23.<\/jats:p>","DOI":"10.3390\/genes14030552","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T03:25:56Z","timestamp":1677122756000},"page":"552","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pathogenicity Analysis of a Novel Variant in GTPBP3 Causing Mitochondrial Disease and Systematic Literature Review"],"prefix":"10.3390","volume":"14","author":[{"given":"Qin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Children\u2019s Hospital of Soochow University, Suzhou 215127, China"},{"name":"Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, China"},{"name":"Center for Reproduction and Genetics, Suzhou Municipal Hospital, Suzhou 215008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6414-3049","authenticated-orcid":false,"given":"Qianqian","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Human Phenome Institute, Zhangjiang Fudan International Innovation Center, MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Xiang","sequence":"additional","affiliation":[{"name":"Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, China"},{"name":"Center for Reproduction and Genetics, Suzhou Municipal Hospital, Suzhou 215008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, China"},{"name":"Center for Reproduction and Genetics, Suzhou Municipal Hospital, Suzhou 215008, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haitao","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Children\u2019s Hospital of Soochow University, Suzhou 215127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8051-8229","authenticated-orcid":false,"given":"Yu","family":"An","sequence":"additional","affiliation":[{"name":"Human Phenome Institute, Zhangjiang Fudan International Innovation Center, MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev-genom-091416-035426","article-title":"Recent Advances in Mitochondrial Disease","volume":"18","author":"Craven","year":"2017","journal-title":"Annu. 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PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0144273"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1038\/s41598-018-19587-5","article-title":"Defects in the mitochondrial-tRNA modification enzymes MTO1 and GTPBP3 promote different metabolic reprogramming through a HIF-PPARgamma-UCP2-AMPK axis","volume":"8","author":"Boutoual","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D971","DOI":"10.1093\/nar\/gkz829","article-title":"PGG.Han: The Han Chinese genome database and analysis platform","volume":"48","author":"Gao","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s00439-020-02115-9","article-title":"De novo variants in the Helicase-C domain of CHD8 are associated with severe phenotypes including autism, language disability and overgrowth","volume":"139","author":"An","year":"2020","journal-title":"Hum. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/3\/552\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:39:34Z","timestamp":1760121574000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/3\/552"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,22]]},"references-count":17,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["genes14030552"],"URL":"https:\/\/doi.org\/10.3390\/genes14030552","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,22]]}}}