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A loss-of-function variant in DNA mismatch repair gene MLH3 underlies severe oligozoospermia

Journal of Human Genetics volume 66, pages 725–730 (2021)Cite this article

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Abstract

Male infertility pertains to male’s inability to cause pregnancy in a fertile female. It accounts for 40–50% of infertility in human. In the study, presented here, a large consanguineous family of Pakistani origin segregating male infertility in autosomal recessive manner was investigated. Exome sequencing revealed a homozygous frameshift variant [NM_001040108: c.3632delA, p.(Asn1211Metfs*49)] in DNA mismatch repair gene MLH3 (MutL Homolog) that segregated with male infertility within the family. This is the first loss-of-function homozygous variant in the MLH3 gene causing severe oligozoospermia leading to male infertility. Previous studies have demonstrated association of infertility with gene knockout in the mice.

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Acknowledgements

We thank the family members for participating in this study.

Funding

This work was supported by the Pakistan Academy of Science, Pakistan (https://www.paspk.org) (PAS-171) to WA.

Author information

Authors and Affiliations

  1. Department of Biotechnology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Shoaib Nawaz & Mehboob Nawaz

  2. Department of Gastroenterology, Hayatabad Medical Complex, Peshawar, KP, Pakistan

    Muhammad Imran Ullah

  3. Department of Obstetrics and Gynecology, KMU Institute of Medical Sciences, Kohat, KP, Pakistan

    Beenish Samreen Hamid

  4. Department of Obstetrics and Gynaecology, Women and Children Teaching Hospital, Kohat, Pakistan

    Beenish Samreen Hamid & Jalwa Nargis

  5. Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Shabir Hussain & Wasim Ahmad

Authors
  1. Shoaib Nawaz
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  2. Muhammad Imran Ullah
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  3. Beenish Samreen Hamid
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  4. Jalwa Nargis
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  5. Mehboob Nawaz
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  6. Shabir Hussain
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  7. Wasim Ahmad
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Contributions

SN designed the study, drafted the manuscript, and performed segregation analysis. SH performed exome data analysis. IU and MN performed the clinical tests. BSH and JN collected the samples and analyzed the clinical data. WA designed the study, provided funds, and edited, and finalized the manuscript. All the authors have approved the final manuscript.

Corresponding author

Correspondence to Wasim Ahmad.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Institutional Review Board (IRB) of Quaid-i-Azam University, Islamabad, Pakistan (IRB# QAU-171). The family, displaying male infertility, was ascertained from Khyber Pakhtunkhwa (KP) province of Pakistan. Informed written consent to carry out the study was obtained from family members.

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Nawaz, S., Ullah, M.I., Hamid, B.S. et al. A loss-of-function variant in DNA mismatch repair gene MLH3 underlies severe oligozoospermia. J Hum Genet 66, 725–730 (2021). https://doi.org/10.1038/s10038-021-00907-z

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  • DOI: https://doi.org/10.1038/s10038-021-00907-z

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