Abstract
Female infertility is a relatively common phenotype with a growing number of single gene causes although these account for only a minority of cases. Here, we report a consanguineous family in which adult females who are homozygous for a truncating variant in ASTL display markedly reduced fertility in a pattern strikingly similar to Astl−/− female mice. ASTL encodes ovastacin, which is known to trigger zona pellucida hardening (ZPH) as part of the cortical reaction upon fertilization. ZPH is required for normal early embryonic development and its absence can be caused by pathogenic variants in other zona pellucida proteins that result in a similar infertility phenotype in humans and mouse. This is the first report of ASTL-related infertility in humans and suggests that the inclusion of ASTL in female infertility gene panels is warranted.
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Alkuraya FS (2013) The application of next-generation sequencing in the autozygosity mapping of human recessive diseases. Hum Genet 132:1197–1211
Anazi S, Maddirevula S, Faqeih E, Alsedairy H, Alzahrani F, Shamseldin HE, Patel N, Hashem M, Ibrahim N, Abdulwahab F, Ewida N, Alsaif HS, Al Sharif H, Alamoudi W, Kentab A, Bashiri FA, Alnaser M, AlWadei AH, Alfadhel M, Eyaid W, Hashem A, Al Asmari A, Saleh MM, AlSaman A, Alhasan KA, Alsughayir M, Al Shammari M, Mahmoud A, Al-Hassnan ZN, Al-Husain M, Osama Khalil R, Abd El Meguid N, Masri A, Ali R, Ben-Omran T, El Fishway P, Hashish A, Ercan Sencicek A, State M, Alazami AM, Salih MA, Altassan N, Arold ST, Abouelhoda M, Wakil SM, Monies D, Shaheen R, Alkuraya FS (2017) Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry 22:615–624. https://doi.org/10.1038/mp.2016.113
Aydin H, Sultana A, Li S, Thavalingam A, Lee JE (2016) Molecular architecture of the human sperm IZUMO1 and egg JUNO fertilization complex. Nature 534:562–565
Burkart AD, Xiong B, Baibakov B, Jiménez-Movilla M, Dean J (2012) Ovastacin, a cortical granule protease, cleaves ZP2 in the zona pellucida to prevent polyspermy Ovastacin cleaves ZP2 and prevents polyspermy. J Cell Biol 197:37–44
Coskun S, Roca GL, Elnour AM, al Mayman H, Hollanders JM, Jaroudi KA, (1998) Effects of reducing insemination time in human in vitro fertilization and embryo development by using sibling oocytes. J Assist Reprod Genet 15:605–608. https://doi.org/10.1023/a:1020333427698
Cuthbertson KR, Cobbold P (1985) Phorbol ester and sperm activate mouse oocytes by inducing sustained oscillations in cell Ca 2+. Nature 316:541–542
Dietzel E, Wessling J, Floehr J, Schäfer C, Ensslen S, Denecke B, Rösing B, Neulen J, Veitinger T, Spehr M (2013) Fetuin-B, a liver-derived plasma protein is essential for fertilization. Dev Cell 25:106–112
Ducibella T, Fissore R (2008) The roles of Ca2+, downstream protein kinases, and oscillatory signaling in regulating fertilization and the activation of development. Dev Biol 315:257–279
Floehr J, Dietzel E, Schmitz C, Chappell A, Jahnen-Dechent W (2016) Down-regulation of the liver-derived plasma protein fetuin-B mediates reversible female infertility. MHR: Basic Sci Reproduct Med 1–11
Gelfman S, Wang Q, McSweeney KM, Ren Z, La Carpia F, Halvorsen M, Schoch K, Ratzon F, Heinzen EL, Boland MJ, Petrovski S, Goldstein DB (2017) Annotating pathogenic non-coding variants in genic regions. Nat Commun 8:236. https://doi.org/10.1038/s41467-017-00141-2
Gianaroli L, Fiorentino A, Magli MC, Ferraretti AP, Montanaro N (1996) Prolonged sperm-oocyte exposure and high sperm concentration affect human embryo viability and pregnancy rate. Hum Reprod 11:2507–2511. https://doi.org/10.1093/oxfordjournals.humrep.a019149
Gomis-Rüth FX, Trillo-Muyo S, Stöcker W (2012) Functional and structural insights into astacin metallopeptidases. Biol Chem 393:1027–1041
Hachem A, Godwin J, Ruas M, Lee HC, Ferrer Buitrago M, Ardestani G, Bassett A, Fox S, Navarrete F, De Sutter P (2017) PLCζ is the physiological trigger of the Ca2+ oscillations that induce embryogenesis in mammals but conception can occur in its absence. Development 144:2914–2924
Human Reproduction (2011) The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reproduct 26:1270–1283
Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, Darbandi SF, Knowles D, Li YI, Kosmicki JA, Arbelaez J, Cui W, Schwartz GB, Chow ED, Kanterakis E, Gao H, Kia A, Batzoglou S, Sanders SJ, Farh KK (2019) Predicting splicing from primary sequence with deep learning. Cell 176(535–548):e24. https://doi.org/10.1016/j.cell.2018.12.015
Jian X, Boerwinkle E, Liu X (2014) In silico prediction of splice-altering single nucleotide variants in the human genome. Nucleic Acids Res 42:13534–13544. https://doi.org/10.1093/nar/gku1206
Körschgen H, Kuske M, Karmilin K, Yiallouros I, Balbach M, Floehr J, Wachten D, Jahnen-Dechent W, Stöcker W (2017) Intracellular activation of ovastacin mediates pre-fertilization hardening of the zona pellucida. MHR: Basic Sci Reproduct Med 23:607–616
Le Bras A, Hesters L, Gallot V, Tallet C, Tachdjian G, Frydman N (2017) Shortening gametes co-incubation time improves live birth rate for couples with a history of fragmented embryos. Syst Biol Reprod Med 63:331–337. https://doi.org/10.1080/19396368.2017.1336581
Maddirevula S, Kuwahara H, Ewida N, Shamseldin HE, Patel N, Alzahrani F, AlSheddi T, AlObeid E, Alenazi M, Alsaif HS (2020) Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics. Genome Biol 21:1–21
Nozawa K, Satouh Y, Fujimoto T, Oji A, Ikawa M (2018) Sperm-borne phospholipase C zeta-1 ensures monospermic fertilization in mice. Sci Rep 8:1–10
Quesada V, Sánchez LM, Álvarez J, López-Otín C (2004) Identification and characterization of human and mouse ovastacin: a novel metalloproteinase similar to hatching enzymes from arthropods, birds, amphibians, and fish. J Biol Chem 279:26627–26634
Rankin T, Familari M, Lee E, Ginsberg A, Dwyer N, Blanchette-Mackie J, Drago J, Westphal H, Dean J (1996) Mice homozygous for an insertional mutation in the Zp3 gene lack a zona pellucida and are infertile. Development 122:2903–2910
Rankin T, Talbot P, Lee E, Dean J (1999) Abnormal zonae pellucidae in mice lacking ZP1 result in early embryonic loss. Development 126:3847–3855
Rankin TL, O’Brien M, Lee E, Wigglesworth K, Eppig J, Dean J (2001) Defective zonae pellucidae in Zp2-null mice disrupt folliculogenesis, fertility and development. Development 128:1119–1126
Stöcker W, Karmilin K, Hildebrand A, Westphal H, Yiallouros I, Weiskirchen R, Dietzel E, Floehr J, Jahnen-Dechent W (2014) Mammalian gamete fusion depends on the inhibition of ovastacin by fetuin-B. Biol Chem 395:1195–1199
Wessel GM, Brooks JM, Green E, Haley S, Voronina E, Wong J, Zaydfudim V, Conner S (2001) The biology of cortical granules. Int Rev Cytol 209:117–206
Xiong B, Zhao Y, Beall S, Sadusky AB, Dean J (2017) A unique egg cortical granule localization motif is required for ovastacin sequestration to prevent premature ZP2 cleavage and ensure female fertility in mice. PLoS Genet 13:e1006580
Zhou Z, Ni C, Wu L, Chen B, Xu Y, Zhang Z, Mu J, Li B, Yan Z, Fu J (2019) Novel mutations in ZP1, ZP2, and ZP3 cause female infertility due to abnormal zona pellucida formation. Hum Genet 138:327–337
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Maddirevula, S., Coskun, S., Al-Qahtani, M. et al. ASTL is mutated in female infertility. Hum Genet 141, 49–54 (2022). https://doi.org/10.1007/s00439-021-02388-8
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DOI: https://doi.org/10.1007/s00439-021-02388-8