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Identification of a new splice-acceptor mutation in HFM1 and functional analysis through molecular docking in nonobstructive azoospermia


Saebnia, Neda; Ebrahimzadeh-Vesal, Reza; Haddad-Mashhadrizeh, Aliakbar; Gholampour-Faroji, Nazanin; Schinzel, Albert; Neshati, Zeinab; Azimi-Nezhad, Mohsen (2022). Identification of a new splice-acceptor mutation in HFM1 and functional analysis through molecular docking in nonobstructive azoospermia. Journal of assisted reproduction and genetics, 39(5):1195-1203.

Abstract

Purpose: To investigate the genetic cause of nonobstructive azoospermia (NOA).
Methods: We performed whole exome sequencing (WES) on the proband who had three relatives suffering from NOA. We used a list of candidate genes which have high expression level in testis and their mutations have been reported in NOA. Sanger sequencing verified the identified variant and its structural and functional consequence was evaluated by protein three-dimensional (3D) structure prediction and protein-ligand docking.
Results: WES revealed a novel splice-acceptor mutation (c.1832-2A>T) in helicase for meiosis 1 (HFM1) gene, which co-segregated with the NOA in this family. 3D structural models were generated and verified. Molecular docking indicated that the c.1832-2A>T mutation affects not only the ADP binding residues but also the hydrogen bond interactions. The ADP binding site will be lost in the mutant protein, potentially causing defective crossover and synapsis.
Conclusion: We report that the c.1832-2A>T mutation is the likely cause of NOA in the family studied. Regarding that many reported NOA genes are involved in the formation of crossovers and synapsis and have critical roles in the production of germ cells, we suggest that such genes should be considered for screening of infertility among large cohorts of infertile individuals.

Abstract

Purpose: To investigate the genetic cause of nonobstructive azoospermia (NOA).
Methods: We performed whole exome sequencing (WES) on the proband who had three relatives suffering from NOA. We used a list of candidate genes which have high expression level in testis and their mutations have been reported in NOA. Sanger sequencing verified the identified variant and its structural and functional consequence was evaluated by protein three-dimensional (3D) structure prediction and protein-ligand docking.
Results: WES revealed a novel splice-acceptor mutation (c.1832-2A>T) in helicase for meiosis 1 (HFM1) gene, which co-segregated with the NOA in this family. 3D structural models were generated and verified. Molecular docking indicated that the c.1832-2A>T mutation affects not only the ADP binding residues but also the hydrogen bond interactions. The ADP binding site will be lost in the mutant protein, potentially causing defective crossover and synapsis.
Conclusion: We report that the c.1832-2A>T mutation is the likely cause of NOA in the family studied. Regarding that many reported NOA genes are involved in the formation of crossovers and synapsis and have critical roles in the production of germ cells, we suggest that such genes should be considered for screening of infertility among large cohorts of infertile individuals.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Reproductive Medicine
Life Sciences > Genetics
Health Sciences > Obstetrics and Gynecology
Life Sciences > Developmental Biology
Health Sciences > Genetics (clinical)
Uncontrolled Keywords:Male infertility, nonobstructive azoospermia, whole exome sequencing, protein modeling, molecular docking, HFM1
Language:English
Date:29 April 2022
Deposited On:21 Jun 2022 08:34
Last Modified:29 Jan 2024 02:41
Publisher:Springer
ISSN:1058-0468
OA Status:Green
Publisher DOI:https://doi.org/10.1007/s10815-022-02433-z
PubMed ID:35486194
Other Identification Number:PMC9107553
  • Content: Supplemental Material
  • Language: English
  • Description: Fig S1
  • Content: Supplemental Material
  • Language: English
  • Description: HIRES Image
  • Content: Supplemental Material
  • Description: Table S1 (MS Excel)