研究開発・学会発表
診療・治療
Comprehensive analysis of infertility related to mitochondrial dysfunction: Identification of SURF1(p.D202H) variant in patients with recurrent ART failures
- IFFS2025
- 2025/4/28～5/1 東京国際フォーラム
- Comprehensive analysis of infertility related to mitochondrial dysfunction: Identification of SURF1(p.D202H) variant in patients with recurrent ART failures
- Xingqiang Wei、Junko Otsuki、Kohyo Furuhashi、Naoki Mukaida、Ryota Okamoto、Saori Yoshimura、Shinichiro Saeki、Mariko Iwamoto、Yumiko Yoshikawa、Kaori Kodera、Ai Yamada、Nao Hayashi、Yihsien Enatsu、Kunihiro Enatsu、Noritoshi Enatsu、Yoko Tokura、Satoshi Yamada、Yuri Mizusawa、Eri Okamoto、Shoji Kokeguchi、Toshiro Iwasaki、Yasuhiro Fujiwara、Mikiya Nakatsuka、Tetsuo Kunied、and Masahide Shiotani
Introduction:
Mutations in mitochondrial DNA are well-known to impair mitochondrial function, which is critical for ATP production. Additionally, mutations in nuclear DNA that affect mitochondrial function can also lead to mitochondrial dysfunction. As diminished mitochondrial function in oocytes may contribute to infertility, this study seeks to conduct a comprehensive genetic analysis to investigate the role of these mutations in infertility.
Methods:
Whole-genome sequencing was conducted on 30 patients with recurrent ART failure and 11 control subjects who successfully delivered. The patient group was subdivided into 11 individuals who eventually achieved live births and 19 who did not. A total of 1,136 mitochondria-related genes from the MitoCarta database were analyzed to identify homozygous variants absent in the successful delivery group. The 14KJPN database from the Tohoku Medical Megabank Organization was used to filter for genes with an allele frequency below 0.05, prioritizing variants deemed deleterious by at least four out of five bioinformatics tools (PolyPhen2, SIFT, MutationTaster, FATHMM, PROVEAN).
Results:
Homozygous missense variants in the genes ECH1 (p.G217R), RDH13 (p.S32G), SURF1 (p.D202H), and ZADH2 (p.K35N) were identified. The homozygous SURF1 (p.D202H) variant, associated with Leigh syndrome, was identified in 10.5% (2/19) of the infertility group, a significantly higher proportion than in the Human Genetic Variation Database (1.2%, 14/1209; P = 0.024). Both affected patients had discontinued ART after more than 30 failed attempts.
Conclusion:
The SURF1 protein, located in the mitochondrial inner membrane, encodes a key assembly factor responsible for stabilizing cytochrome c oxidase (COX) in the human electron transport chain. Over 60 distinct SURF1 variants have been implicated in Leigh syndrome. The SURF1 (p.D202H) homozygous variant identified in this study has also been observed in patients with Leigh syndrome. However, evidence suggests that transfection of SURF1-deficient cells with the SURF1 (p.D202H) variant can restore both SURF1 stability and COX activity, implying a potentially neutral association between this variant and Leigh syndrome. Nonetheless, the possibility of impaired embryonic development or post-implantation fetal growth associated with the SURF1 (p.D202H) homozygous variant remains unresolved, warranting further investigation.
