SURF1 p.D202H variant is not associated with Leigh syndrome but may contribute to impaired pregnancy outcomes

IF 1 Q4 GENETICS & HEREDITY

Gene Reports Pub Date : 2025-04-29 DOI:10.1016/j.genrep.2025.102240

Xingqiang Wei , Junko Otsuki , Miki Fujii , Kaori Kodera , Ai Yamada , Nao Hayashi , Yihsien Enatsu , Kunihiro Enatsu , Noritoshi Enatsu , Yoko Tokura , Satoshi Yamada , Yuri Mizusawa , Eri Okamoto , Shoji Kokeguchi , Toshiroh Iwasaki , Yasuhiro Fujiwara , Mikiya Nakatsuka , Tetsuo Kunieda , Masahide Shiotani

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引用次数: 0

Abstract

The SURF1 gene encodes a mitochondrial protein critical for cytochrome c oxidase (COX) assembly. The c.604G>C (p.D202H) variant, identified in the homozygous state, has conflicting pathogenicity classifications in ClinVar and was found in 6.7 % of individuals with recurrent ART failure or pregnancy loss. This study included 30 Japanese women with infertility, 25 with recurrent ART failure and 5 with recurrent pregnancy loss, and 23 Japanese women with normal fertility, including 12 with successful ART outcomes and 11 with natural conception histories. The median ages of the infertility and control groups were 41.5 and 36 years, respectively. Participants were recruited from Hanabusa Women's Clinic and Okayama University Hospital. Whole-exome sequencing (WES) was performed using DNA extracted from peripheral blood mononuclear cells. Variant prioritization focused on 1136 mitochondrial-related nuclear genes listed in the MitoCarta3.0 database. Analysis was restricted to homozygous missense variants absent in the control group and with minor allele frequency < 0.05 in Japanese databases. SURF1 (p.D202H) was significantly enriched in the infertility group compared to population databases. Structural modeling with AlphaFold2 and ChimeraX revealed local hydrogen bonding alterations caused by the substitution of aspartate with histidine at position 202. These findings suggest that while p.D202H is not pathogenic for Leigh syndrome, it may contribute to mitochondrial dysfunction in reproductive tissues. Further investigation into its tissue-specific effects is warranted.

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SURF1 p.D202H变异与Leigh综合征无关，但可能导致妊娠结局受损

SURF1基因编码一种线粒体蛋白，对细胞色素c氧化酶（COX）组装至关重要。在纯合子状态下发现的C . 604g>C （p.D202H）变异在ClinVar中具有相互矛盾的致病性分类，在6.7%的复发性ART失败或妊娠失败的个体中发现。本研究纳入30名日本不孕女性，25名ART复发失败女性，5名复发妊娠丢失女性，以及23名生育能力正常的日本女性，其中12名ART成功，11名有自然受孕史。不孕症组和对照组的中位年龄分别为41.5岁和36岁。参与者从花丛妇女诊所和冈山大学医院招募。全外显子组测序（WES）采用提取外周血单个核细胞的DNA。变异优先排序集中在MitoCarta3.0数据库中列出的1136个线粒体相关核基因上。分析仅限于对照组中不存在的纯合错义变异，等位基因频率较小；日本数据库0.05。与人群数据库相比，不育组的SURF1 （p.D202H）显著富集。利用AlphaFold2和ChimeraX进行结构建模，揭示了202位组氨酸取代天冬氨酸导致的局部氢键改变。这些发现表明，虽然p.D202H对Leigh综合征没有致病作用，但它可能导致生殖组织中的线粒体功能障碍。对其组织特异性效应的进一步研究是有必要的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.