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A novel pathogenic mitochondrial DNA variant m.4344T>C in tRNAGln causes developmental delay

Journal of Human Genetics volume 69, pages 381–389 (2024)Cite this article

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Abstract

Mitochondrial diseases are a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA. However, the genetic spectrum of this disease is not yet complete. In this study, we identified a novel variant m.4344T>C in mitochondrial tRNAGln from a patient with developmental delay. The mutant loads of m.4344T>C were 95% and 89% in the patient’s blood and oral epithelial cells, respectively. Multialignment analysis showed high evolutionary conservation of this nucleotide. TrRosettaRNA predicted that m.4344T>C variant would introduce an additional hydrogen bond and alter the conformation of the T-loop. The transmitochondrial cybrid-based study demonstrated that m.4344T>C variant impaired the steady-state level of mitochondrial tRNAGln and decreased the contents of mitochondrial OXPHOS complexes I, III, and IV, resulting in defective mitochondrial respiration, elevated mitochondrial ROS production, reduced mitochondrial membrane potential and decreased mitochondrial ATP levels. Altogether, this is the first report in patient carrying the m.4344T>C variant. Our data uncover the pathogenesis of the m.4344T>C variant and expand the genetic mutation spectrum of mitochondrial diseases, thus contributing to the clinical diagnosis of mitochondrial tRNAGln gene variants-associated mitochondrial diseases.

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Acknowledgements

We sincerely thank the patient and his family who participated in the study. This work was supported by grants from the National Natural Science Foundation of China-excellent young scientists fund (No. 82222043), the Natural Science Foundation of China (No. U22A20342 and 82302636), the “Pioneer” and “Leading Goose” R&D Program of Zhejiang Province (No. 2024C03152), Zhejiang Provincial Natural Science Foundation (No. LQ23H200001), Scientific Research Fund of Zhejiang Provincial Education Department (No. Y202249698), Shanghai Municipal Commission of Health and Family Planning (No. 20204Y0451), Shanghai Scientific and Technological Innovation Action Plan (No.21YF1437800), Shanghai Natural Science Foundation of China (No.21ZR1452700) and the Science and Technology Bureau of Wenzhou (No.Y2023089).

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  1. These authors contributed equally: Xiaojie Yin, Qiyu Dong

Authors and Affiliations

  1. Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Xiaojie Yin, Qiyu Dong, Shuanglong Fan, Lina Yang, Hao Li, Yijun Jin, Mahlatsi Refiloe Laurentinah, Hezhi Fang, Jianxin Lyu & Ya Wang

  2. International Sakharov Environmental Institute of Belarusian State University, Minsk, 220070, Republic of Belarus

    Xiandan Chen & Aliaksei Sysa

  3. Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310053, Zhejiang, China

    Jianxin Lyu

  4. Department of Pediatric Endocrinology and Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai, 200092, China

    Yongguo Yu

  5. Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, 200092, China

    Yongguo Yu

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Correspondence to Jianxin Lyu, Yongguo Yu or Ya Wang.

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Yin, X., Dong, Q., Fan, S. et al. A novel pathogenic mitochondrial DNA variant m.4344T>C in tRNAGln causes developmental delay. J Hum Genet 69, 381–389 (2024). https://doi.org/10.1038/s10038-024-01254-5

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