Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees
Abstract Background GTPBP3 catalyzes τm5(s2) U biosynthesis at the 34th wobble position of mitochondrial tRNAs, the hypomodification of τm5U leads to mitochondrial disease. While twenty-three variants of GTPBP3 have been reported worldwide, the genetic landscape in China remains uncertain. Methods B...
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2024-12-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | https://doi.org/10.1186/s13023-024-03469-3 |
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| author | Yaojun Xie Keyi Li Li Yang Xiaofei Zeng Zhehui Chen Xue Ma Luyi Zhang Yuwei Zhou Liqin Jin Yanling Yang Xiaoting Lou |
| author_facet | Yaojun Xie Keyi Li Li Yang Xiaofei Zeng Zhehui Chen Xue Ma Luyi Zhang Yuwei Zhou Liqin Jin Yanling Yang Xiaoting Lou |
| author_sort | Yaojun Xie |
| collection | DOAJ |
| description | Abstract Background GTPBP3 catalyzes τm5(s2) U biosynthesis at the 34th wobble position of mitochondrial tRNAs, the hypomodification of τm5U leads to mitochondrial disease. While twenty-three variants of GTPBP3 have been reported worldwide, the genetic landscape in China remains uncertain. Methods By using whole-exome sequencing, the candidate individuals carrying GTPBP3 variants were screened and identified. Pathogenicity analysis of variants was biochemically verified by patients-derived immortalized lymphocytes and cell models. Results Through whole-exome sequencing, thirteen variants associated with GTPBP3 were identified in nine Chinese pedigrees, with eight of these variants being newly reported. Affected individuals displayed classic neurologic phenotypes and heart complications including developmental delay, seizures, hypotonia, exercise intolerance, and hypertrophic cardiomyopathy. Additionally, they displayed new symptoms such as eye problems like strabismus and heart issues related to valve function. Studies conducted on patient-derived cells provided evidence of reduced levels of GTPBP3 and impairment in mitochondrial energetic biogenesis. Re-expressing GTPBP3 variants in knockout cell lines further defined the pathogenicity of the novel variants. Analysis of the genetic spectrum in the Chinese population highlighted a concentration in exons 4 and 6, with c.689A > C being the prominent hotspot. Conclusion Our findings emphasize the extensive clinical and genetic implications of GTPBP3-related mitochondrial disorders, particularly within the Chinese population, but further investigations are needed to explore the phenotype-genotype correlation. |
| format | Article |
| id | doaj-art-84e5e9d756b84c1586ccc40d3efb681c |
| institution | DOAJ |
| issn | 1750-1172 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj-art-84e5e9d756b84c1586ccc40d3efb681c2025-08-20T02:39:37ZengBMCOrphanet Journal of Rare Diseases1750-11722024-12-0119111310.1186/s13023-024-03469-3Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigreesYaojun Xie0Keyi Li1Li Yang2Xiaofei Zeng3Zhehui Chen4Xue Ma5Luyi Zhang6Yuwei Zhou7Liqin Jin8Yanling Yang9Xiaoting Lou10Laboratory Medicine Center, Department of Genetic and Genomic Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeKey Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Pediatrics, Clinical Research Center for Children Neurodevelopmental Disabilities of Hunan Province, Xiangya Hospital, Central South UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Pediatrics, Peking University First HospitalDepartment of Pediatrics, Peking University First HospitalKey Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Scientific Research, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeDepartment of Pediatrics, Peking University First HospitalLaboratory Medicine Center, Department of Genetic and Genomic Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeAbstract Background GTPBP3 catalyzes τm5(s2) U biosynthesis at the 34th wobble position of mitochondrial tRNAs, the hypomodification of τm5U leads to mitochondrial disease. While twenty-three variants of GTPBP3 have been reported worldwide, the genetic landscape in China remains uncertain. Methods By using whole-exome sequencing, the candidate individuals carrying GTPBP3 variants were screened and identified. Pathogenicity analysis of variants was biochemically verified by patients-derived immortalized lymphocytes and cell models. Results Through whole-exome sequencing, thirteen variants associated with GTPBP3 were identified in nine Chinese pedigrees, with eight of these variants being newly reported. Affected individuals displayed classic neurologic phenotypes and heart complications including developmental delay, seizures, hypotonia, exercise intolerance, and hypertrophic cardiomyopathy. Additionally, they displayed new symptoms such as eye problems like strabismus and heart issues related to valve function. Studies conducted on patient-derived cells provided evidence of reduced levels of GTPBP3 and impairment in mitochondrial energetic biogenesis. Re-expressing GTPBP3 variants in knockout cell lines further defined the pathogenicity of the novel variants. Analysis of the genetic spectrum in the Chinese population highlighted a concentration in exons 4 and 6, with c.689A > C being the prominent hotspot. Conclusion Our findings emphasize the extensive clinical and genetic implications of GTPBP3-related mitochondrial disorders, particularly within the Chinese population, but further investigations are needed to explore the phenotype-genotype correlation.https://doi.org/10.1186/s13023-024-03469-3Mitochondrial diseasesOxidative phosphorylationGTPBP3Genetic hotspotτm5(s2)U modification |
| spellingShingle | Yaojun Xie Keyi Li Li Yang Xiaofei Zeng Zhehui Chen Xue Ma Luyi Zhang Yuwei Zhou Liqin Jin Yanling Yang Xiaoting Lou Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees Orphanet Journal of Rare Diseases Mitochondrial diseases Oxidative phosphorylation GTPBP3 Genetic hotspot τm5(s2)U modification |
| title | Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees |
| title_full | Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees |
| title_fullStr | Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees |
| title_full_unstemmed | Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees |
| title_short | Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees |
| title_sort | expanding the phenotypic and genetic spectrum of gtpbp3 deficiency findings from nine chinese pedigrees |
| topic | Mitochondrial diseases Oxidative phosphorylation GTPBP3 Genetic hotspot τm5(s2)U modification |
| url | https://doi.org/10.1186/s13023-024-03469-3 |
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