AK9 缺乏会通过破坏精子核苷酸动态平衡导致弱精症和男性不育。

Deficiency in AK9 causes asthenozoospermia and male infertility by destabilising sperm nucleotide homeostasis.

机构信息

Department of Andrology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, Fujian, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian, China.

NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, Guangdong, China.

出版信息

EBioMedicine. 2023 Oct;96:104798. doi: 10.1016/j.ebiom.2023.104798. Epub 2023 Sep 13.

DOI:10.1016/j.ebiom.2023.104798

PMID:37713809

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10507140/

Abstract

BACKGROUND

Asthenozoospermia is the primary cause of male infertility; however, its genetic aetiology remains poorly understood. Adenylate kinase 9 (AK9) is highly expressed in the testes of humans and mice and encodes a type of adenosine kinase that is functionally involved in cellular nucleotide homeostasis and energy metabolism. We aimed to assess whether AK9 is involved in asthenozoospermia.

METHODS

One-hundred-and-sixty-five Chinese men with idiopathic asthenozoospermia were recruited. Whole-exome sequencing (WES) and Sanger sequencing were performed for genetic analyses. Papanicolaou staining, Haematoxylin and eosin staining, scanning electron microscopy, and transmission electron microscopy were used to observe the sperm morphology and structure. Ak9-knockout mice were generated using CRISPR-Cas9. Sperm adenosine was detected by liquid chromatography-mass spectrometry. Targeted sperm metabolomics was performed. Intracytoplasmic sperm injection (ICSI) was used to treat patients.

FINDINGS

We identified five patients harbouring bi-allelic AK9 mutations. Spermatozoa from men harbouring bi-allelic AK9 mutations have a decreased ability to sustain nucleotide homeostasis. Moreover, bi-allelic AK9 mutations inhibit glycolysis in sperm. Ak9-knockout male mice also presented similar phenotypes of asthenozoospermia. Interestingly, ICSI was effective in bi-allelic AK9 mutant patients in achieving good pregnancy outcomes.

INTERPRETATION

Defects in AK9 induce asthenozoospermia with defects in nucleotide homeostasis and energy metabolism. This sterile phenotype could be rescued by ICSI.

FUNDING

The National Natural Science Foundation of China (82071697), Medical Innovation Project of Fujian Province (2020-CXB-051), open project of the NHC Key Laboratory of Male Reproduction and Genetics in Guangzhou (KF202004), Medical Research Foundation of Guangdong Province (A2021269), Guangdong Provincial Reproductive Science Institute Innovation Team grants (C-03), and Outstanding Young Talents Program of Capital Medical University (B2205).

摘要

背景

弱精症是男性不育的主要原因，但遗传病因仍知之甚少。腺苷激酶 9（AK9）在人和小鼠的睾丸中高度表达，编码一种腺苷激酶，其功能参与细胞核苷酸稳态和能量代谢。我们旨在评估 AK9 是否与弱精症有关。

方法

招募了 165 名患有特发性弱精症的中国男性。进行全外显子组测序（WES）和 Sanger 测序进行遗传分析。巴氏染色、苏木精-伊红染色、扫描电子显微镜和透射电子显微镜用于观察精子形态和结构。使用 CRISPR-Cas9 生成 Ak9 敲除小鼠。通过液相色谱-质谱法检测精子腺苷。进行靶向精子代谢组学分析。使用胞浆内单精子注射（ICSI）治疗患者。