2. Academic Validation
  3. A novel homozygous mutation in WDR19 induces disorganization of microtubules in sperm flagella and nonsyndromic asthenoteratospermia

A novel homozygous mutation in WDR19 induces disorganization of microtubules in sperm flagella and nonsyndromic asthenoteratospermia

  • J Assist Reprod Genet. 2020 Jun;37(6):1431-1439. doi: 10.1007/s10815-020-01770-1.
Xiaoqing Ni 1 2 3,  Jiajia Wang 1 2 3,  Mingrong Lv 1 4 5,  Chunyu Liu 6 7 8,  Yading Zhong 9,  Shixiong Tian 6 7 8,  Huan Wu 1 2 3,  Huiru Cheng 1 2 3,  Yang Gao 1 2 3,  Qing Tan 1 2 3,  Beili Chen 1 2 3,  Qiang Li 4 5,  Bing Song 1 4 5,  Zhaolian Wei 1 2 3,  Ping Zhou 1 2 3,  Xiaojin He 10 11 12,  Feng Zhang 13 14 15,  Yunxia Cao 16 17 18
Affiliations

Affiliations

  • 1 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 2 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China.
  • 3 Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China.
  • 4 Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, China.
  • 5 Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, 230022, China.
  • 6 Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, 200011, China.
  • 7 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.
  • 8 State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211116, China.
  • 9 Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 10 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. [email protected].
  • 11 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China. [email protected].
  • 12 Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China. [email protected].
  • 13 Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, 200011, China. [email protected].
  • 14 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China. [email protected].
  • 15 State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211116, China. [email protected].
  • 16 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. [email protected].
  • 17 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China. [email protected].
  • 18 Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China. [email protected].
PMID: 32323121 DOI: 10.1007/s10815-020-01770-1
Abstract

Background: Asthenoteratospermia with multiple morphological abnormalities in the sperm flagella (MMAF) is a significant cause of male infertility. WDR19 is a core component in the IFT-A complex and has a critical role in intraflagellar transport. However, the role of WDR19 mutations in male infertility has yet to be examined.

Methods and results: We performed whole exome sequencing (WES) for 65 asthenoteratospermia individuals and identified a proband who carried a homozygous WDR19 (c.A3811G, p.K1271E) mutation from a consanguineous family. Systematic examinations, including CT scanning and retinal imaging, excluded previous ciliopathic syndromes in the proband. Moreover, semen analysis of this patient showed that the progressive rate decreased to zero, and the sperm flagella showed multiple morphological abnormalities. Scanning and transmission electron microscopy assays indicated that the ultrastructure of sperm flagella in the patient was completely destroyed, while immunofluorescence revealed that WDR19 was absent from the sperm neck and flagella. Moreover, IFT140 and IFT88, predicted to interact with WDR19 directly, were mis-allocated in the WDR19-mutated sperm. Notably, the MMAF subject harboring WDR19 variant and his partner successfully achieved clinical pregnancy through intracytoplasmic sperm injection (ICSI).

Conclusions: We identified WDR19 as a novel pathogenic gene for male infertility caused by asthenoteratospermia in the absence of other ciliopathic phenotypes, and that patients carrying WDR19 variant can have favorable pregnancy outcomes following ICSI.

Keywords

Asthenoteratospermia; Flagellum; Intracytoplasmic sperm injection; WDR19; Whole exome sequencing.

Figures