Research question

Male infertility is a widespread symptom in patients with primary ciliary dyskinesia (PCD). PCD-related male infertility is often caused by asthenozoospermia, with barely normal sperm morphology. Multiple morphological abnormalities of the sperm flagella (MMAF) are a major cause of asthenozoospermia, characterized by various malformed morphologies of sperm flagella. To date, a limited number of genes have been suggested to be involved in the pathogenesis of both PCD and MMAF. What other genes associated with both PCD and MMAF are waiting to be discovered?

Design

Whole-exome sequencing (WES) was performed to identify the pathogenic mutation associated with MMAF in a PCD patient. Peripheral venous blood and semen samples were collected from the PCD patient. Transmission electron microscopy (TEM), immunofluorescence staining and western blotting were conducted to confirm the pathogenicity of the identified mutation.

Results

A novel homozygous mutation in CCDC39, c.983 T>C (p. Leu328Pro), was identified in two PCD-affected siblings of a consanguineous family showing a typical PCD phenotype, while the proband was infertile, which is associated with characterized MMAF. Furthermore, TEM revealed the abnormal ultrastructure of the patient's sperm flagella. Moreover, immunofluorescence staining revealed that CCDC39 was almost undetectable in the spermatozoa, which was further confirmed by western blotting. The outcome of intracytoplasmic sperm injection (ICSI) in the patient with the CCDC39 mutation was also favourable.

Conclusion

This study demonstrates that a novel loss-of-function mutation of CCDC39 is involved in the pathogenesis of PCD and MMAF and initially reported that ICSI treatment has a good outcome. Therefore, the novel variant of CCDC39 contributes to the genetic diagnosis, counselling and treatment of male infertility in PCD patients with MMAF phenotype.

中文翻译：

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一种新的 CCDC39 突变导致原发性纤毛运动障碍患者鞭毛的多种形态异常

研究问题

男性不育是原发性纤毛运动障碍 (PCD) 患者的普遍症状。PCD 相关的男性不育症通常是由弱精子症引起的，精子形态几乎不正常。精子鞭毛的多种形态异常（MMAF）是弱精子症的主要原因，其特征是精子鞭毛的各种畸形形态。迄今为止，已经提出有限数量的基因参与 PCD 和 MMAF 的发病机制。还有哪些与 PCD 和 MMAF 相关的基因有待被发现？

设计

进行了全外显子组测序 (WES) 以确定与 PCD 患者 MMAF 相关的致病突变。从 PCD 患者收集外周静脉血和精液样本。进行透射电子显微镜（TEM）、免疫荧光染色和蛋白质印迹以确认所鉴定突变的致病性。

结果

在 CCDC39 中发现了一个新的纯合突变， c.983 T>C (p. Leu328Pro)，在显示典型 PCD 表型的近亲家族的两个受 PCD 影响的兄弟姐妹中发现，而先证者不育，这与特征性 MMAF 相关。此外，TEM显示患者精子鞭毛的异常超微结构。此外，免疫荧光染色显示精子中几乎检测不到 CCDC39，蛋白质印迹进一步证实了这一点。CCDC39突变患者的胞浆内精子注射（ICSI）的结果也是有利的。

结论

该研究表明，CCDC39的一种新的功能丧失突变参与了 PCD 和 MMAF 的发病机制，并初步报道了 ICSI 治疗具有良好的结果。因此，CCDC39的新变体有助于对具有 MMAF 表型的 PCD 患者的男性不育症进行基因诊断、咨询和治疗。