Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
J Med Genet. 2022 Jul;59(7):710-718. doi: 10.1136/jmedgenet-2021-107919. Epub 2021 Aug 4.
Oligoasthenoteratozoospermia is a typical feature of sperm malformations leading to male infertility. Only a few genes have been clearly identified as pathogenic genes of oligoasthenoteratozoospermia.
Here, we identified a homozygous frameshift variant (c.731dup, p.Asn244Lysfs3) in , which is preferentially expressed in the human testis, using whole-exome sequencing in a cohort of 100 Chinese men with multiple morphological abnormalities of the sperm flagella (MMAF). In an additional cohort of 167 MMAF-affected men from North Africa, Iran and France, we identified a second subject harbouring a homozygous frameshift variant (c.799_817del, p.Glu267Lysfs72). Both affected men presented a typical MMAF phenotype with an abnormally low sperm concentration (ie, oligoasthenoteratozoospermia). Transmission electron microscopy analysis of the sperm flagella affected by deficiency further revealed dramatic disorganisation of the axoneme. Immunofluorescence assays of the spermatozoa showed that deficiency resulted in almost absent staining of CCDC34 and intraflagellar transport-B complex-associated proteins (such as IFT20 and IFT52). Furthermore, we generated a mouse frameshift mutant using CRISPR-Cas9 technology. -mutated ( ) male mice were sterile and presented oligoasthenoteratozoospermia with typical MMAF anomalies. Intracytoplasmic sperm injection has good pregnancy outcomes in both humans and mice.
Our findings support that is crucial to the formation of sperm flagella and that biallelic deleterious mutations in / cause male infertility with oligoasthenoteratozoospermia in humans and mice.
少弱畸形精子症是导致男性不育的精子畸形的典型特征。只有少数几个基因被明确鉴定为少弱畸形精子症的致病基因。
在这里，我们通过对 100 名具有多种精子鞭毛形态异常（MMAF）的中国男性进行全外显子组测序，发现了一个纯合移码变异（c.731dup，p.Asn244Lysfs3），该变异在人类睾丸中优先表达。在来自北非、伊朗和法国的另外 167 名 MMAF 受累男性的队列中，我们发现了第二个携带纯合移码变异（c.799_817del，p.Glu267Lysfs72）的个体。两名受影响的男性均表现出典型的 MMAF 表型，精子浓度异常低（即少弱畸形精子症）。对 缺乏引起的精子鞭毛的透射电子显微镜分析进一步显示轴丝结构严重紊乱。精子的免疫荧光分析表明， 缺乏导致 CCDC34 和鞭毛内运输-B 复合物相关蛋白（如 IFT20 和 IFT52）几乎不存在染色。此外，我们使用 CRISPR-Cas9 技术生成了一个 移码突变的小鼠模型。 使用 CRISPR-Cas9 技术生成了一个 移码突变的小鼠模型。 - 突变（ ）雄性小鼠不育，表现出典型的 MMAF 异常和少弱畸形精子症。胞浆内单精子注射在人和小鼠中都有良好的妊娠结局。
我们的研究结果支持 对于精子鞭毛的形成至关重要，并且 / 中的双等位基因有害突变导致人类和小鼠的少弱畸形精子症引起男性不育。
