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Novel DNAAF6 variants identified by whole-exome sequencing cause male infertility and primary ciliary dyskinesia

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To identify the genetic cause of patients with primary ciliary dyskinesia (PCD) and male infertility from two unrelated Han Chinese families.

Methods

We conducted whole-exome sequencing of three individuals with PCD and male infertility from two unrelated Chinese families, and performed a targeted look-up for DNAAF6 variants in our previously reported cohort of 442 individuals (219 with isolated oligoasthenospermia and 223 fertile controls). Ultrastructural and immunostaining analyses of patients’ spermatozoa were performed. The pathogenicity of the variants was validated using patient’s spermatozoa and HEK293T cells. Intracytoplasmic sperm injection (ICSI) treatment was conducted in two patients.

Results

We identified one novel hemizygous frameshift variant (NM_173494, c.319_329del: p.R107fs) of DNAAF6 gene (previously named PIH1D3) in family 1 and one novel hemizygous missense variant (c.290G>T: p.G97V) in family 2. No hemizygous deleterious variants in DNAAF6 were detected in the control cohort of 442 individuals. Ultrastructural and immunostaining analyses of patients’ spermatozoa showed the absence of outer and inner dynein arms in sperm flagella. Both variants were proven to lead to DNAAF6 protein degradation in HEK293T cells. Both patients carrying DNAAF6 variants underwent one ICSI cycle and delivered one healthy child each.

Conclusion

We identified novel DNAAF6 variants causing male infertility and PCD in Han Chinese patients. This finding extended the spectrum of variants in DNAAF6 and revealed new light on the impact of DNAAF6 variants in sperm flagella.

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Data availability

The data and material that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgments

The authors would like to thank all the families and individuals who participated in this study. We are grateful to the excellent technical support provided by Junpu Wang, as well as support from the clinical and nursing staff at the Reproductive and Genetic Hospital of CITIC-Xiangya.

Funding

This work was supported by the National Key Research & Developmental Program of China (2018YFC1004900 to YQ.T), the National Natural Science Foundation of China (81771645 and 81971447 to YQ.T), the science and technology major project of the Ministry of Science and Technology of Hunan Province (2017SK1030 to YQ.T), the China Postdoctoral Science Foundation Funded Project (2019M662786 to CF.T), and the Graduate Research and Innovation Projects of Central South University (2019zzts998 to Y.W).

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Author notes

  1. Ying Wang and Chaofeng Tu contributed equally to this work.

Authors and Affiliations

  1. Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China

    Ying Wang, Chaofeng Tu, Hongchuan Nie, Dongyan Li, Weili Wang, Guangxiu Lu & Ge Lin

  2. Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China

    Chaofeng Tu, Hongchuan Nie, Lanlan Meng, Huan Zhang, Guangxiu Lu, Ge Lin, Yue-Qiu Tan & Juan Du

  3. National Engineering and Research Center of Human Stem Cell, Changsha, China

    Guangxiu Lu & Ge Lin

  4. Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha, 410078, Hunan, China

    Yue-Qiu Tan & Juan Du

Authors
  1. Ying Wang
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  2. Chaofeng Tu
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  3. Hongchuan Nie
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  4. Lanlan Meng
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  11. Juan Du
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Contributions

Juan Du and Yue-Qiu Tan designed the study. Lanlan Meng, Dongyan Li, and Weili Wang performed the variant analysis. Ying Wang and Chaofeng Tu carried out the evaluation of the pathogenicity of variations and spermatozoa functional analyses. Hongchuan Nie, Huan Zhang, Guangxiu Lu, and Ge Lin worked on the clinical study. Ying Wang, Chaofeng Tu, Yue-Qiu Tan, and Juan Du wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yue-Qiu Tan or Juan Du.

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Wang, Y., Tu, C., Nie, H. et al. Novel DNAAF6 variants identified by whole-exome sequencing cause male infertility and primary ciliary dyskinesia. J Assist Reprod Genet 37, 811–820 (2020). https://doi.org/10.1007/s10815-020-01735-4

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  • DOI: https://doi.org/10.1007/s10815-020-01735-4

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