Deleterious mutation in SYCE1 is associated with non-obstructive azoospermia
Abstract
Purpose
To determine the molecular basis of familial, autosomal-recessive, non-obstructive azoospermia in a consanguineous Iranian Jewish family.
Methods
We investigated the genetic cause of non-obstructive azoospermia in two affected siblings from a consanguineous family. Homozygosity mapping in the DNA samples of the patients and their normospermic brother was followed by exome analysis of one of the patients. Other family members were genotyped for the mutation by Sanger sequencing. The mutation effect was demonstrated by immunostaining of the patients’ testicular tissue.
Results
The two patients were homozygous for a splice site mutation in SYCE1 which resulted in retention of intron three in the cDNA and premature stop codon. SYCE1 encodes a Synaptonemal Complex protein which plays an essential role during meiosis. Immunostaining of patient’s testicular tissue with anti-Syce1 antibody revealed an undetectable level of Syce1. Histological examination of the patients’ tissue disclosed immature-stages spermatocytes without mature forms, indicating maturation arrest.
Conclusion
The significance of most synaptonemal complex proteins was previously demonstrated in a mutant mouse model. The present report underscores the importance of synaptonemal complex proteins in spermatogenenesis in humans. Our new approach, combining homozygosity mapping and exome sequencing, resulted in one of the first reports of an autosomal-recessive form of NOA.
Keywords
Meiosis Azoospermia Maturation arrest Exome sequencingNotes
Acknowledgment
We wish to thank Vivi Zuri Naama Lexner and Olga Genin for excellent technical assistance.
Conflict of interest
The authors have no conflict of interest to declare.
Contributor statement
YC, BY, AS, HG, SZ, CR, OE and AF conceived and designed the experiments; EMS, YC, BY, AS, HG, and SZ performed the experiments; all the coauthors analyzed the data and participated in the writing of the paper; EMS undertook patient management, collection of samples, and delineation of the phenotype. The research was supported in part by a grant from the Joint Research Fund of the Hebrew University and Hadassah.
References
- 1.Anderson JE, Farr SL, Jamieson DJ, Warner L, Macaluso M. Infertility services reported by men in the United States: national survey data. Fertil Steril. 2009;91:2466–70.PubMedCrossRefGoogle Scholar
- 2.Jarvi K et al. CUA guideline: the workup of azoospermic males. Can Urol Assoc J. 2010;4:163–7.PubMedCentralPubMedCrossRefGoogle Scholar
- 3.Vogt PH, Edelmann A, Kirsch S, et al. Human Y chromosome azoospermia factors (AZF) mapped to different suregions in Yq11. Hum Mol Genet. 1996;5:933.PubMedCrossRefGoogle Scholar
- 4.Miyamoto T et al. Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet. 2003;362:1714–9.PubMedCrossRefGoogle Scholar
- 5.Ayhan O, Balkan M, Guven A, Hazan R, Atar M, Tok A, et al. Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia. J Med Genet. 2014. doi: 10.1136/jmedgenet-2013-102102.PubMedGoogle Scholar
- 6.Page SL, Hawley RS. The genetics and molecular biology of the synaptonemal complex. Annu Rev Cell Dev Biol. 2004;20:525–58.PubMedCrossRefGoogle Scholar
- 7.Bolcun-Filas E et al. Mutation of the mouse Syce1 gene disrupts synapsis and suggests a link between synaptonemal complex structural components and DNA repair. PLoS Genet. 2009;5:e1000393.PubMedCentralPubMedCrossRefGoogle Scholar
- 8.McGuire MM, Bowden W, Engel NJ, Ahn HW, Kovanci E, Rajkovic A. Genomic analysis using high-resolution single-nucleotide polymorphism arrays reveals novel microdeletions associated with premature ovarian failure. Fertil Steril. 2011;95:1595–600.PubMedCentralPubMedCrossRefGoogle Scholar
- 9.Vries LD, Behar DM, Smirin-Yosef P, Lagovsky I, Tzur S, Basel-Vanagaite L. Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency. J Clin Endocrinol Metab. 2014;25:jc20141268.Google Scholar
- 10.Edvardson S et al. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet. 2007;81:857–62.PubMedCentralPubMedCrossRefGoogle Scholar
- 11.Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. Mutation Taster evaluates disease causing potential of sequence alterations. Nat Methods. 2010;7:575–6.PubMedCrossRefGoogle Scholar
- 12.Schramm S et al. A novel mouse synaptonemal complex protein is essential for loading of central element proteins, recombination, and fertility. PLoS Genet. 2011;7:e1002088.PubMedCentralPubMedCrossRefGoogle Scholar