School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China.
Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, China.
J Med Genet. 2019 Oct;56(10):678-684. doi: 10.1136/jmedgenet-2018-105952. Epub 2019 May 31.
Multiple morphological abnormalities of the sperm flagella (MMAF) is a kind of severe teratozoospermia. Patients with the MMAF phenotype are infertile and present aberrant spermatozoa with absent, short, coiled, bent and/or irregular flagella. Mutations in several genes can explain approximately 30%-50% of MMAF cases and more genetic pathogenies need to be explored. SPEF2 was previously demonstrated to play an essential role in sperm tail development in mice and pig. Dysfunctional mutations in impair sperm motility and cause a short-tail phenotype in both animal models.
Based on 42 patients with severe infertility and MMAF phenotype, we explored the new genetic cause of human MMAF phenotype.
By screening gene variants in 42 patients with MMAF using whole exome sequencing, we identified the c. 12delC, c. 1745-2A > G, c. 4102 G > T and c. 4323dupA mutations in the gene from two patients. Both of these mutations are rare and potentially deleterious. Transmission electron microscope (TEM) analysis showed a disrupted axonemal structure with mitochondrial sheath defects in the patients' spermatozoa. The SPEF2 protein level was significantly decreased in the spermatozoa of the patients revealed by Western blot (WB) and immunofluorescence (IF) analyses.
Our experimental findings indicate that loss-of-function mutations in the gene can cause the MMAF phenotype in human.
精子鞭毛多发形态异常（MMAF）是一种严重的畸形精子症。具有 MMAF 表型的患者不育，其精子表现为鞭毛缺失、短小、卷曲、弯曲和/或不规则。几种基因的突变可以解释大约 30%-50%的 MMAF 病例，需要进一步探索更多的遗传病因。SPEF2 先前被证明在小鼠和猪的精子尾部发育中发挥重要作用。在这两种动物模型中，功能失调的突变会导致精子运动功能障碍，并引起短尾表型。
基于 42 名严重不育和 MMAF 表型的患者，我们探讨了人类 MMAF 表型的新遗传病因。
通过对 42 名 MMAF 患者进行全外显子组测序，我们在两名患者的 基因中发现了 c.12delC、c.1745-2A>G、c.4102G>T 和 c.4323dupA 突变。这两种突变均为罕见的潜在有害突变。透射电子显微镜（TEM）分析显示，患者精子的轴丝结构被破坏，线粒体鞘存在缺陷。Western blot（WB）和免疫荧光（IF）分析显示，患者精子中的 SPEF2 蛋白水平显著降低。
我们的实验结果表明， 基因的功能丧失突变可导致人类 MMAF 表型。
