Xie Yaojun, Li Keyi, Yang Li, Zeng Xiaofei, Chen Zhehui, Ma Xue, Zhang Luyi, Zhou Yuwei, Jin Liqin, Yang Yanling, Lou Xiaoting
Laboratory Medicine Center, Department of Genetic and Genomic Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Genetics Center of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
Orphanet J Rare Dis. 2024 Dec 24;19(1):488. doi: 10.1186/s13023-024-03469-3.
GTPBP3 catalyzes τm(s) U biosynthesis at the 34th wobble position of mitochondrial tRNAs, the hypomodification of τmU leads to mitochondrial disease. While twenty-three variants of GTPBP3 have been reported worldwide, the genetic landscape in China remains uncertain.
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.
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.
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.
GTPBP3在线粒体tRNA的第34位摆动位置催化τm(s)U生物合成，τmU的低甲基化会导致线粒体疾病。虽然全球已报道了23种GTPBP3变体，但中国的遗传情况仍不明确。
通过全外显子测序筛选并鉴定携带GTPBP3变体的候选个体。通过患者来源的永生化淋巴细胞和细胞模型对变体的致病性进行生化验证。
通过全外显子测序，在9个中国家系中鉴定出13种与GTPBP3相关的变体，其中8种是新报道的。受影响个体表现出典型的神经表型和心脏并发症，包括发育迟缓、癫痫发作、肌张力减退、运动不耐受和肥厚型心肌病。此外，他们还表现出斜视等眼部问题和与瓣膜功能相关的心脏问题等新症状。对患者来源细胞的研究提供了GTPBP3水平降低和线粒体能量生物合成受损的证据。在敲除细胞系中重新表达GTPBP3变体进一步明确了新变体的致病性。对中国人群遗传谱的分析突出了外显子4和6的集中情况，其中c.689A>C是主要热点。
我们的研究结果强调了GTPBP3相关线粒体疾病广泛的临床和遗传意义，特别是在中国人群中，但需要进一步研究以探索表型-基因型相关性。
