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Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF)
  1. Wensheng Liu1,
  2. Yanwei Sha2,
  3. Yang Li1,
  4. Libin Mei2,
  5. Shaobin Lin2,
  6. Xianjing Huang2,
  7. Jinhua Lu3,
  8. Lu Ding2,
  9. Shuangbo Kong3,
  10. Zhongxian Lu1
  1. 1 School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
  2. 2 Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, China
  3. 3 Fujian Provincial Key Laboratory of Reproductive Health Research, Medical College of Xiamen University, Xiamen University, Xiamen, China
  1. Correspondence to Dr Zhongxian Lu, School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen 361102, China; zhongxian{at}


Background 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 SPEF2 impair sperm motility and cause a short-tail phenotype in both animal models.

Objective Based on 42 patients with severe infertility and MMAF phenotype, we explored the new genetic cause of human MMAF phenotype.

Methods and results 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 SPEF2 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.

Conclusion Our experimental findings indicate that loss-of-function mutations in the SPEF2 gene can cause the MMAF phenotype in human.

  • whole-exome sequence
  • human infertility
  • multiple morphological abnormalities of flagella

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  • WL, YS and YL contributed equally.

  • Contributors WL: performed the genetic analyses and molecular experiments; YS: recruited the family and obtained the clinical samples and information; YL: wrote the manuscript; L-BM: performed the sperm analysis; SL: performed the data analysis; X-JH: performed the data analysis; JL: performed the sperm analysis; LD: designed the study and collected the data; SK: designed the study and edited the manuscript; ZL: designed the study, coordinated the research and edited the manuscript.

  • Funding This work was supported by the following grants: the open project of Key Laboratory of Male Reproduction and Genetics, National Health and Family Planning Commission(Grant No. KF201704, No. KF201807; the Medicine and Health Science Technology Development Project of Shandong Province (Grant No. 2016WS0704); Natural Science Foundation of Shandong Province (Grant No. ZR2017LH012); the National Natural Science Foundation of China (Grant No. 31171375 and No. 81871200); the Science Technology Guidance Project of Fujian Province (Grant No. 2017D018); the Linqiaozhi Funding Supporting Youth Project of Xiamen Maternity and Child Care Hospital (Grant No. FYLQZ2015004).

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval This study was approved by the Ethics Committees at the Xiamen Maternity and Child Care Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request.