• PMID: 31119281
• Gene Name: ADCY10
• Condition: Asthenozoospermia
• Association: Associated
• Mutation: c.1205_1206del, rs779944215, p.His402Argfs*41
• Population size: 20
• Population details: 20 (10 normozoospermic men, 10 asthenozoospermic patients)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

ADCY10 frameshift variant leading to severe recessive asthenozoospermia and segregating with absorptive hypercalciuria

Akbari A, Pipitone GB, Anvar Z, Jaafarinia M, Ferrari M, Carrera P, Totonchi M.

STUDY QUESTION: Can whole exome sequencing (WES) reveal a novel pathogenic variant in asthenozoospermia in a multiplex family including multiple patients? SUMMARY ANSWER: Patients were discovered to be homozygous for a rare 2-bp deletion in the ADCY10 coding region (c.1205_1206del, rs779944215). WHAT IS KNOWN ALREADY: ADCY10 encodes for soluble adenylyl cyclase (sAC), which is the predominant adenylate cyclase in sperm. It is already established that proper sAC activity and a constant supply of cAMP are crucial to sperm motility regulation, and knockout mouse models have been reported as severely asthenozoospermic. ADCY10 is a susceptibility gene for dominant absorptive hypercalciuria (OMIM#143870); however, no ADCY10 variations have been confirmed to cause human asthenozoospermia to date. STUDY DESIGN, SIZE, DURATION: This was a retrospective genetics study of a highly consanguineous pedigree of asthenozoospermia. The subject family was recruited in Iran in 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The two patients were diagnosed as asthenozoospermic through careful clinical investigations. Both patients, respective parents, and an unaffected brother were subjected to WES. The discovered variant was validated by Sanger sequencing and segregated with the phenotype. To confirm the pathogenicity of the variant, sperm samples from both patients, 10 normozoospermic men and 10 asthenozoospermic patients not representing the variation, were treated with a cAMP analogue dissolved in human tubal fluid medium, followed by computer-assisted sperm analysis and statistical analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The discovered homozygous variant occurs at 10 amino acids upstream of the ADCY10 nucleotide binding site leading to a premature termination (p.His402Argfs*41). Treatment of the patients' sperm samples with a cell-permeable cAMP analogue resulted in a significant increase in sperm motility, indicating the pathogenic role of the variant. Moreover, absorptive hypercalciuria, segregating within the family, was also associated with the same variant following a dominant inheritance. LIMITATIONS, REASONS FOR CAUTION: Though nonsense-mediated decay is highly likely to occur in the mutated transcripts, we were not able to confirm this due to low RNA levels in mature sperm. WIDER IMPLICATIONS OF THE FINDINGS: Our finding enlarges the phenotypic spectrum associated with the ADCY10 gene, previously described as a susceptibility gene for dominant absorptive hypercalciuria. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Royan Institute, Tehran, Iran, and San Raffaele Hospital, Milan, Italy. The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A. CI - © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Akbari, Arvand AU - Akbari A AD - Department of Biology, Faculty of Science, Fars Science and Research Branch, Islamic Azad University, Marvdasht, Iran. AD - Department of Biology, Faculty of Science, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran. FAU - Pipitone, Giovanni Battista AU - Pipitone GB AD - Laboratory of Clinical Molecular Biology and Cytogenetics, IRCCS San Raffaele Hospital, Milan, Italy. FAU - Anvar, Zahra AU - Anvar Z AD - Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. AD - Department of Obstetrics & Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. FAU - Jaafarinia, Mojtaba AU - Jaafarinia M AD - Department of Biology, Faculty of Science, Fars Science and Research Branch, Islamic Azad University, Marvdasht, Iran. AD - Department of Biology, Faculty of Science, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran. FAU - Ferrari, Maurizio AU - Ferrari M AD - Laboratory of Clinical Molecular Biology and Cytogenetics, IRCCS San Raffaele Hospital, Milan, Italy. AD - Genomic Unit for the Diagnosis of Human Disorders, Division of Genetics and Cell Biology, IRCCS San Raffaele Hospital, Milan, Italy. AD - Vita-Salute San Raffaele University, Milan, Italy. FAU - Carrera, Paola AU - Carrera P AD - Laboratory of Clinical Molecular Biology and Cytogenetics, IRCCS San Raffaele Hospital, Milan, Italy. AD - Genomic Unit for the Diagnosis of Human Disorders, Division of Genetics and Cell Biology, IRCCS San Raffaele Hospital, Milan, Italy.