Human Genetics

, Volume 138, Issue 2, pp 125–140 | Cite as

New insights into the genetics of spermatogenic failure: a review of the literature

  • Rossella CannarellaEmail author
  • Rosita A. Condorelli
  • Ylenia Duca
  • Sandro La Vignera
  • Aldo E. CalogeroEmail author


Genetic anomalies are known to affect about 15% of infertile patients with azoospermia or severe oligozoospermia. Despite a throughout diagnostic work-up, in up to the 72% of the male partners of infertile couples, no etiological factor can be found; hence, the cause of infertility remains unclear. Recently, several novel genetic causes of spermatogenic failure (SPGF) have been described. The aim of this review was to collect all the available evidence of SPGF genetics, matching data from in-vitro and animal models with those in human beings to provide a comprehensive and updated overview of the genes capable of affecting spermatogenesis. By reviewing the literature, we provided a list of 60 candidate genes for SPGF. Their investigation by Next Generation Sequencing in large cohorts of patients with apparently idiopathic infertility would provide new interesting data about their racial- and ethnic-related prevalence in infertile patients, likely raising the diagnostic yields. We propose a phenotype-based approach to identify the genes to look for.


Author contributions

RC: conception and design of the study, data acquisition, analysis and interpretation of data, drafting and writing of the article, and final approval of the manuscript. RAC: data acquisition, analysis and interpretation of data, and final approval of the manuscript. YD: data acquisition, analysis and interpretation of data, and final approval of the manuscript. SLV: data acquisition, analysis and interpretation of data, and final approval of the manuscript. AEC: conception and design of the study, analysis and interpretation of data, critical final revision of the manuscript, and final approval of the manuscript.


This research did not receive any specific Grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests in this study.

Supplementary material

439_2019_1974_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 20 KB)


  1. Adelman CA, Petrini JH (2008) ZIP4H (TEX11) deficiency in the mouse impairs meiotic double strand break repair and the regulation of crossing over. PLoS Genet 4(3):e1000042Google Scholar
  2. Amiri-Yekta A, Coutton C, Kherraf ZE, Karaouzène T, Le Tanno P, Sanati MH, Sabbaghian M, Almadani N, Sadighi Gilani MA, Hosseini SH, Bahrami S, Daneshipour A, Bini M, Arnoult C, Colombo R, Gourabi H, Ray PF (2016) Whole-exome sequencing of familial cases of multiple morphological abnormalities of the sperm flagella (MMAF) reveals new DNAH1 mutations. Hum Reprod 31(12):2872–2880Google Scholar
  3. Asero P, Calogero AE, Condorelli RA, Mongioì L, Vicari E, Lanzafame F, Crisci R, La Vignera S (2014) Relevance of genetic investigation in male infertility. J Endocrinol Invest 37(5):415–427Google Scholar
  4. Avenarius MR, Hildebrand MS, Zhang Y, Meyer NC, Smith LLH, Kahrizi K, Najmabadi H, Smith RJH (2009) Human male infertility caused by mutations in the CATSPER1 channel protein. Am J Hum Genet 84:505–510Google Scholar
  5. Ayhan O, Balkan M, Guven A, Hazan R, Atar M, Tok A, Tolun A (2014) Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia. J Med Genet 51:239–244Google Scholar
  6. Bashamboo A, Ferraz-de-Souza B, Lourenco D, Lin L, Sebire NJ, Montjean D, Bignon-Topalovic J, Mandelbaum J, Siffroi J-P, Christin-Maitre S, Radhakrishna U, Rouba H, Ravel C, Seeler J, Achermann JC, McElreavey K (2010) Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1. Am J Hum Genet 87:505–512Google Scholar
  7. Ben Khelifa M, Zouari R, Harbuz R, Halouani L, Arnoult C, Lunardi J, Ray PF (2011) A new AURKC mutation causing macrozoospermia: implications for human spermatogenesis and clinical diagnosis. Molec Hum Reprod 17:762–768Google Scholar
  8. Ben Khelifa M, Coutton C, Zouari R, Karaouzene T, Rendu J, Bidart M, Yassine S, Pierre V, Delaroche J, Hennebicq S, Grunwald D, Escalier D, Pernet-Gallay K, Jouk P-S, Thierry-Mieg N, Toure A, Arnoult C, Ray PF (2014) Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Am J Hum Genet 94:95–104Google Scholar
  9. Blatch GL, Lässle M (1999) The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. BioEssays 21(11):932–939Google Scholar
  10. Bochkareva E, Korolev S, Lees-Miller SP, Bochkarev A (2002) Structure of the RPA trimerization core and its role in the multistep DNA-binding mechanism of RPA. EMBO J 21:1855–1863Google Scholar
  11. Bolcun-Filas E, Hall E, Speed R, Taggart M, Grey C, de Massy B, Benavente R, Cooke HJ (2009) Mutation of the mouse Syce1 gene disrupts synapsis and suggests a link between synaptonemal complex structural components and DNA repair. PLoS Genet 5:e1000393Google Scholar
  12. Butts SF, Seifer DB (2010) Racial and ethnic differences in reproductive potential across the life cycle. Fertil Steril 93(3):681–690Google Scholar
  13. Chao Liu Z, Song L, Wang H, Yu W, Liu Y, Shang Z, Xu H, Zhao F, Gao J, Wen L, Zhao Y, Gui J, Gao JF, Li W (2017) Sirt1 regulates acrosome biogenesis by modulating autophagic flux during spermiogenesis in mice. Development 144:441–451Google Scholar
  14. Chen SR, Liu YX (2015) Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling. Reproduction 149(4):R159–R167Google Scholar
  15. Choi Y, Jeon S, Choi M, Lee M, Park M, Lee DR, Jun KY, Kwon Y, Lee O-H, Song SH, Kim JY, Lee K-A, Yoon TK, Rajkovic A, Shim SH (2010) Mutations in SOHLH1 gene associate with nonobstructive azoospermia. Hum Mutat 31:788–793Google Scholar
  16. Colombo R, Pontoglio A, Bini M (2017) Two novel TEX15 mutations in a family with nonobstructive azoospermia. Gynecol Obstet Invest 2(3):283–286Google Scholar
  17. Coutton C, Vargas AS, Amiri-Yekta A, Kherraf Z-E, Ben Mustapha SF, Le Tanno P, Wambergue-Legrand C, Karaouzene T, Martinez G, Crouzy S, Daneshipour A, Hosseini SH, Mitchell V et al (2018) Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in trypanosoma and human. Nat Commun 9:686Google Scholar
  18. Dam AHDM, Koscinski I, Kremer JAM, Moutou C, Jaeger AS, Oudakker AR, Tournaye H, Charlet N, Lagier-Tourenne C, van Bokhoven H, Viville S (2007) Homozygous mutation in SPATA16 is associated with male infertility in human globozoospermia. Am J Hum Genet 81:813–820Google Scholar
  19. Dieterich K, Rifo RS, Faure AK, Hennebicq S, Amar BB, Zahi M, Perrin J, Martinez D, Sele B, Jouk PS, Ohlmann T, Rousseaux S, Lunardi J, Ray PF (2007) Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat Genet 39:661–665Google Scholar
  20. Dieterich K, Zouari R, Harbuz R, Vialard F, Martinez D, Bellayou H, Prisant N, Zoghmar A, Guichaoua MR, Koscinski I, Kharouf M, Noruzinia M et al (2009) The aurora kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population. Hum Mol Genet 18:1301–1309Google Scholar
  21. Dirami T, Rode B, Jollivet M, Da Silva N, Escalier D, Gaitch N, Norez C, Tuffery P, Wolf J-P, Becq F, Ray PF, Dulioust E, Gacon G, Bienvenu T, Toure A (2013) Missense mutations in SLC26A8, encoding a sperm-specific activator of CFTR, are associated with human asthenozoospermia. Am J Hum Genet 92:760–766Google Scholar
  22. Dong FN, Amiri-Yekta A, Martinez G, Saut A, Tek J, Stouvenel L, Lores P, Karaouzene T, Thierry-Mieg N, Satre V, Brouillet S, Daneshipour A et al (2018) Absence of CFAP69 cause male infertility due to multiple morphological abnormalities of the flagella in human and mouse. Am J Hum Genet 102:636–648Google Scholar
  23. El Khouri E, Thomas L, Jeanson L, Bequignon E, Vallette B, Duquesnoy P, Montantin G, Copin B, Dastot-Le Moal F, Blanchon S, Papon JF, Lorès P, Yuan L, Collot N, Tissier S, Faucon C, Gacon G et al (2016) Mutations in DNAJB13, encoding an HSP40 family member, cause primary ciliary dyskinesia and male infertility. Am J Hum Genet 99(2):489–500Google Scholar
  24. Ellnati E, Kuentz P, Redin C, Jaber S, Vanden Meerschaut F, Makarian J, Koscinski I, Nasr-Esfahani MH, Demirol A, Gurgan T, Louanjli N, Iqbal N et al (2012) Globozoospermia is mainly due to DPY19L2 deletion via non-allelic homologous recombination involving two recombination hotspots. Hum Mol Genet 21:3695–3702Google Scholar
  25. Falender AE, Freiman RN, Geles KG, Lo KC, Hwang K, Lamb DJ, Morris PL, Tjian R, Richards JS (2005) Maintenance of spermatogenesis requires TAF4b, a gonad-specific subunit of TFIID. Genes Dev 19(7):794–803Google Scholar
  26. Ferlin A, Rocca MS, Vinanzi C, Ghezzi M, Di Nisio A, Foresta C (2015) Mutational screening of NR5A1 gene encoding steroidogenic factor 1 in cryptorchidism and male factor infertility and functional analysis of seven undescribed mutations. Fertil Steril 104(1):163.e1–119.e1Google Scholar
  27. Fischer S, Kohlhase J, Bohm D, Schweiger B, Hoffmann D, Heitmann M, Horsthemke B, Wieczorek D (2008) Biallelic loss of function of the promyelocytic leukaemia zinc finger (PLZF) gene causes severe skeletal defects and genital hypoplasia. J Med Genet 45:731–737Google Scholar
  28. Foresta C, Moro E, Garolla A, Onisto M, Ferlin A (1999) Y chromosome microdeletions in cryptorchidism and idiopathic infertility. J Clin Endocr Metab 84:3660–3665Google Scholar
  29. Foresta C, Ferlin A, Moro E (2000) Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility. Hum Mol Genet 9:1161–1169Google Scholar
  30. Fraune J, Schramm S, Alsheimer M, Benavente R (2012) The mammalian synaptonemal complex: protein components, assembly and role in meiotic recombination. Exp Cell Res 318(12):1340–1346Google Scholar
  31. Freiman RN, Albright SR, Zheng S, Sha WC, Hammer RE, Tjian R (2001) Requirement of tissue-selective TBP-associated factor TAFII105 in ovarian development. Science 293(5537):2084–2087Google Scholar
  32. Gegenschatz-Schmid K, Verkauskas G, Demougin P, Bilius V, Dasevicius D, Stadler MB, Hadziselimovic F (2018) Curative GnRHa treatment has an unexpected repressive effect on Sertoli cell specific genes. Basic Clin Androl 28:2Google Scholar
  33. Gershoni M, Hauser R, Yogev L, Lehavi O, Azem F, Yavetz H, Pietrokovski S, Kleiman SE (2017) A familial study of azoospermic men identifies three novel causative mutations in three new human azoospermia genes. Genet Med 19(9):998–1006Google Scholar
  34. Greenbaum MP, Yan W, Wu MH, Lin YN, Agno JE, Sharma M, Braun RE, Rajkovic A, Matzuk MM (2006) TEX14 is essential for intercellular bridges and fertility in male mice. Proc Natl Acad Sci USA 103(13):4982–4987Google Scholar
  35. Harbuz R, Zouari R, Pierre V, Ben Khelifa M, Kharouf M, Coutton C, Merdassi G, Abada F, Escoffier J, Nikas Y, Vialard F, Koscinski I, Triki C, Sermondade N, Schweitzer T, Zhioua A et al (2011) A recurrent deletion of DPY19L2 causes infertility in man by blocking sperm head elongation and acrosome formation. Am J Hum Genet 88:351–361Google Scholar
  36. Harris RM, Weiss J, Jameson JL (2011) Male hypogonadism and germ cell loss caused by a mutation in polo-like kinase 4. Endocrinology 152:3975–3985Google Scholar
  37. Hashemi MS, Mozdarani H, Ghaedi K, Nasr-Esfahani MH (2018) Expression of ZMYND15 in testes of azoospermic men and association with sperm retrieval. Urology 114:99–104Google Scholar
  38. He WB, Tu CF, Liu Q, Meng LL, Yuan SM, Luo AX, He FS, Shen J, Li W, Du J, Zhong CG, Lu GX, Lin G, Fan LQ, Tan YQ (2018) DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing. J Med Genet 55(3):198–204Google Scholar
  39. Huang N, Wen Y, Guo X, Li Z, Dai J, Ni B, Yu J, Lin Y, Zhou W, Yao B, Jiang Y, Sha J, Conrad DF, Hu Z (2015) A screen for genomic disorders of infertility identifies MAST2 duplications associated with nonobstructive azoospermia in humans. Biol Reprod 93:61Google Scholar
  40. Ji ZY, Sha YW, Ding L, Li P (2017) Genetic factors contributing to human primary ciliary dyskinesia and male infertility. Asian J Androl 19(5):515–520Google Scholar
  41. Julaton VT, Reijo Pera RA (2011) NANOS3 function in human germ cell development. Hum Mol Genet 20(11):2238–2250Google Scholar
  42. Kalfa N, Gaspari L, Ollivier M, Philibert P, Bergougnoux A, Paris F, Sultan C (2019) Molecular genetics of hypospadias and cryptorchidism recent developments. Clin Genet 95(1):122–131Google Scholar
  43. Kallio M, Chang Y, Manuel M, Alastalo T-P, Rallu M, Gitton Y, Pirkkala L, Loones M-T, Paslaru L, Larney S, Hiard S, Morange M, Sistonen L, Mezger V (2002) Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice. EMBO J 21:2591–2601Google Scholar
  44. Kasak L, Punab M, Nagirmaja L, Grigorova M, Minajeva A, Lopes AM, Punab AM, Aston KI, Carvalho F, Laasik E, Smith LB, GEMINI Consortium, Conrad DF, Laan M (2018) Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia. Am J Hum Genet 103:200–212Google Scholar
  45. Kay BK, Williamson MP, Sudol M (2000) The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. FASEB J 14(2):231–241Google Scholar
  46. Kherraf Z-E, Christou-Kent M, Karaouzene T, Amiri-Yekta A, Martinez G, Vargas AS, Lambert E, Borel C, Dorphin B, Aknin-Seifer I, Mitchell MJ, Metzler-Guillemain C et al (2017) SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes. EMBO Mol Med 9:1132–1149Google Scholar
  47. Kherraf ZE, Amiri-Yekta A, Dacheux D, Karaouzene T, Coutton C, Christou-Kent M, Martinez G, Landrein N, Le Tanno P, Mustapha SFB, Halouani L, Marrakchi O et al (2018) A homozygous ancestral SVA-insertion-mediated deletion in WDR66 induces multiple morphological abnormalities of the sperm flagellum and male infertility. Am J Hum Genet 103:400–412Google Scholar
  48. Kim HJ, Yoon J, Matsuura A, Na JH, Lee WK, Kim H, Choi JW, Park JE, Park SJ, Kim KT, Chang R, Lee BI, Yu YG, Shin YK, Jeong C, Rhee K, Lee HH (2015) Structural and biochemical insights into the role of testis-expressed gene 14 (TEX14) in forming the stable intercellular bridges of germ cells. Proc Natl Acad Sci USA 112(40):12372–12377Google Scholar
  49. Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, Turnpenny P, Winter RM, Reardon W (2002) Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet 11:2979–2987Google Scholar
  50. Koscinski I, ElInati E, Fossard C, Redin C, Muller J, Velez de la Calle JV, Schmitt F, Ben Khelifa M, Ray PF, Kilani Z, Barratt CLR, Viville S (2011) DPY19L2 deletion as a major cause of globozoospermia. Am J Hum Genet 88:344–350Google Scholar
  51. Kotov AA, Olenkina OM, Godneeva BK, Adashev VE, Olenina LV (2017) Progress in understanding the molecular functions of DDX3Y (DBY) in male germ cell development and maintenance. Biosci Trends 11(1):46–53Google Scholar
  52. Kumar TR (2017) The SO(H)L(H) ‘O’ drivers of oocyte growth and survival but not meiosis I. J Clin Invest 127:2044–2047Google Scholar
  53. Kuo YC, Lin YH, Chen HI, Wang YY, Chiou YW, Lin HH, Pan HA, Wu CM, Su SM, Hsu CC, Kuo PL (2012) SEPT12 mutations cause male infertility with defective sperm annulus. Hum Mutat 33:710–719Google Scholar
  54. Kusz KM, Tomczyk L, Sajek M, Spik A, Latos-Bielenska A, Jedrzejczak P, Pawelczyk L, Jaruzelska J (2009) The highly conserved NANOS2 protein: testis-specific expression and significance for the human male reproduction. Mol Hum Reprod 15:165–171Google Scholar
  55. Kusz-Zamelczyk K, Sajek M, Spik A, Glazar R, Jedrzejczak P, Latos-Bielenska A, Kotecki M, Pawelczyk L, Jaruzelska J (2013) Mutations of NANOS1, a human homologue of the Drosophila morphogen, are associated with a lack of germ cells in testes or severe oligo-astheno-teratozoospermia. J Med Genet 50:187–193Google Scholar
  56. Lawo S, Bashkurov M, Mullin M, Gomez Ferreria M, Kittler R, Habermann B, Tagliaferro A, Poser I, Hutchins JRA, Hegemann B, Pinchev D, Buchholz F, Peters JM, Hyman AA, Gingras AC, Pelletier L (2009) HAUS, the 8-subunit human augmin complex, regulates centrosome and spindle integrity. Curr Biol 19:816–826Google Scholar
  57. Li L, Sha Y, Wang X, Li P, Wang J, Kee K, Wang B (2017) Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa. Oncotarget 8:19914–19922Google Scholar
  58. Li L, Sha YW, Su ZY, Mei LB, Ji ZY, Zhang Q, Lin SB, Wang X, Qiu PP, Li P, Yin C (2018a) A novel mutation in HAUS7 results in severe oligozoospermia in two brothers. Gene 639:106–110Google Scholar
  59. Li L, Sha YW, Xu X, Mei LB, Qiu PP, Ji ZY, Lin SB, Su ZY, Wang C, Yin C, Li P (2018b) DNAH6 is a novel candidate gene associated with sperm head anomaly. Andrologia. (Epub ahead of print) Google Scholar
  60. Liao HF, Chen WS, Chen YH, Kao TH, Tseng YT, Lee CY, Chiu YC, Lee PL, Lin QJ, Ching YH (2014) DNMT3L promotes quiescence in postnatal spermatogonial progenitor cells. Development 141:2402–2413Google Scholar
  61. Lin L, Achermann JC (2008) Steroidogenic factor-1 (SF-1, Ad4BP, NR5A1) and disorders of testis development. Sex Dev 2:200–209Google Scholar
  62. Lin YW, Hsu TH, Yen PH (2011a) Localization of ubiquitin specific protease 26 at blood-testis barrier and near Sertoli cell-germ cell interface in mouse testes. Int J Androl 34(5 Pt 2):e368–e377Google Scholar
  63. Lin YH, Chou CK, Hung YC, Yu IS, Pan HA, Lin SW, Kuo PL (2011b) SEPT12 deficiency causes sperm nucleus damage and developmental arrest of preimplantation embryos. Fertil Steril 95:363–365Google Scholar
  64. Lopes AM, Aston KI, Thompson E et al (2013) Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1. PLoS Genet 9:e1003349Google Scholar
  65. Lores P, Coutton C, El Khouri E, Stouvenel L, Givelet M, Thomas L, Rode B, Schmitt A, Louis B, Sakheli Z, Chaudhry M, Fernandez-Gonzales A et al (2018) Homozygous missense mutation L673P in adenylate kinase 7 (AK7) leads to primary male infertility and multiple morphological anomalies of the flagella but not to primary ciliary dyskinesia. Hum Mol Genet 27:1196–1211Google Scholar
  66. Lourenco D, Brauner R, Lin L, De Perdigo A, Weryha G, Muresan M, Boudjenah R, Guerra-Junior G, Maciel-Guerra AT, Achermann JC, McElreavey K, Bashamboo A (2009) Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 360:1200–1210Google Scholar
  67. Luddi A, Margollicci M, Gambera L, Serafini F, Cioni M, De Leo V, Balestri P, Piomboni P (2009) Spermatogenesis in a man with complete deletion of USP9Y. New Eng J Med 360:881–885Google Scholar
  68. Luo M, Yang F, Leu NA, Landaiche J, Handel MA, Benavente R, La Salle S, Wang PJ (2013) MEIOB exhibits single-stranded DNA-binding and exonuclease activities and is essential for meiotic recombination. Nat Commun 4:2788Google Scholar
  69. Ma Q, Li Y, Guo H, Li C, Chen J, Luo M, Jiang Z, Li H, Gui Y (2016) A novel missense mutation in USP26 gene is associated with nonobstructive azoospermia. Reprod Sci 23:1434–1441Google Scholar
  70. Maor-Sagie E, Cinnamon Y, Yaacov B, Shaag A, Goldsmidt H, Zenvirt S, Laufer N, Richler C, Frumkin A (2015) Deleterious mutation in SYCE1 is associated with non-obstructive azoospermia. J Assist Reprod Genet 32:887–891Google Scholar
  71. Martinez G, Kherraf Z-E, Zouari R, Fourati Ben Mustapha S, Saut A, Pernet-Gallay K, Bertrand A, Bidart M, Hograindleur JP, Amiri-Yekta A, Kharouf M, Karaouzene T, Thierry-Mieg N, Dacheux-Deschamps D, Satre V, Bonhivers M, Toure A, Arnoult C, Ray PF, Coutton C (2018) Whole-exome sequencing identifies mutations in FSIP2 as a recurrent cause of multiple morphological abnormalities of the sperm flagella. Hum Reprod 33:1973–1984Google Scholar
  72. Mata M, Lluch-Estelles J, Armengot M, Sarrion I, Carda C, Cortijo J (2012) New adenylate kinase 7 (AK7) mutation in primary ciliary dyskinesia. Am J Rhinol Allergy 26:260–264Google Scholar
  73. Matson CK, Murphy MW, Griswold MD, Yoshida S, Bardwell VJ, Zarkower D (2010) The mammalian doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells. Dev Cell 19:612–624Google Scholar
  74. Miller MP, Amon A, Ünal E (2013) Meiosis I: when chromosomes undergo extreme makeover. Curr Opin Cell Biol 25(6):687–696Google Scholar
  75. Miyamoto T, Hasuike S, Yogev L, Maduro MR, Ishikawa M, Westphal H, Lamb DJ (2003) Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet 362(9397):1714–1719Google Scholar
  76. Miyamoto T, Bando Y, Koh E, Tsujimura A, Miyagawa Y, Iijima M, Namiki M, Shiina M, Ogata K, Matsumoto N, Sengoku K (2016) A PLK4 mutation causing azoospermia in a man with Sertoli cell-only syndrome. Andrology 4(1):75–81Google Scholar
  77. Mou L, Wang Y, Li H, Huang Y, Jiang T, Huang W, Li Z, Chen J, Xie J, Liu Y, Jiang Z, Li X, Ye J, Cai Z, Gui Y (2013) A dominant-negative mutation of HSF2 associated with idiopathic azoospermia. Hum Genet 132(2):159–165Google Scholar
  78. Mozdarani H, Ghoraeian P, Mozdarani S, Fallahi P, Mohseni-Meybodi A (2018) High frequency of de novo DAZ microdeletion in sperm nuclei of subfertile men: possible involvement of genome instability in idiopathic male infertility. Hum Fertil (Camb) 21(2):137–145Google Scholar
  79. Nakamura S, Miyado M, Saito K, Katsumi M, Nakamura A, Kobori Y, Tanaka Y, Ishikawa H, Yoshida A, Okada H, Hata K, Nakabayashi K, Okamura K, Ogata H, Matsubara Y, Ogata T, Nakai H, Fukami M (2017) Next-generation sequencing for patients with non-obstructive azoospermia: implications for significant roles of monogenic/oligogenic mutations. Andrology 5(4):824–831Google Scholar
  80. Neale MJ, Keeney S (2006) Clarifying the mechanics of DNA strand exchange in meiotic recombination. Nature 442:153–158Google Scholar
  81. Neto FT, Bach PV, Najari BB, Li PS, Goldstein M (2016) Genetics of male infertility. Curr Urol Rep 17(10):70Google Scholar
  82. Okutman O, Muller J, Baert Y, Serdarogullari M, Gultomruk M, Piton A, Rombaut C, Benkhalifa M, Teletin M, Skory V, Bakircioglu E, Goossens E, Bahceci M, Viville S (2015) Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family. Hum Mol Genet 24(19):5581–5588Google Scholar
  83. Paff T, Loges NT, Aprea I, Wu K, Bakey Z, Haarman EG, Daniels JMA, Sistermans EA, Bogunovic N, Dougherty GW, Höben IM, Große-Onnebrink J, Matter A, Olbrich H, Werner C, Pals G, Schmidts M, Omran H, Micha D (2017) Mutations in PIH1D3 cause X-linked primary ciliary dyskinesia with outer and inner dynein arm defects. Am J Hum Genet 100(1):160–168Google Scholar
  84. Pawlowski WP, Cande WZ (2005) Coordinating the events of the meiotic prophase. Trends Cell Biol 15:674–681Google Scholar
  85. Potter SJ, De Falco T (2017) Role of the testis interstitial compartment in spermatogonial stem cell function. Reproduction 153:151–162Google Scholar
  86. Punab M, Poolamets O, Paju P, Vihljajev V, Pomm K, Ladva R, Korrovits P, Laan M (2017) Causes of male infertility: a 9-year prospective monocentre study on 1737 patients with reduced total sperm counts. Hum Reprod 32(1):18–31Google Scholar
  87. Ramathal C, Angulo B, Sukhwani M, Cui J, Durruthy Durruthy J, Fang F, Schanes P, Turek PJ, Orwig KE, Reijo Pera R (2015) DDX3Y gene rescue of a Y chromosome AZFa deletion restores germ cell formation and transcriptional programs. Sci Rep 5:15041Google Scholar
  88. Ravel C, El Houate B, Chantot S, Lourenco D, Dumaine A, Rouba H, Bandyopadahyay A, Radhakrishna U, Das B, Sengupta S, Mandelbaum J, Siffroi JP, McElreavey K (2006) Haplotypes, mutations and male fertility: the story of the testis-specific ubiquitin protease USP26. Mol Hum Reprod 12:643–646Google Scholar
  89. Ren ZJ, Ren PW, Yang B, Liao J, Liu SZ, Fang K, Ren SQ, Liu LR, Dong Q (2017) The SPO11-C631T gene polymorphism and male infertility risk: a meta-analysis. Ren Fail 39(1):299–305Google Scholar
  90. Robert T, Nore A, Brun C, Maffre C, Crimi B, Guichard V, Bourbon HM, de Massy B (2016) The TopoVIB-like protein family is required for meiotic DNA double-strand break formation. Science 351:943–949Google Scholar
  91. Sato H, Miyamoto T, Yogev L, Namiki M, Koh E, Hayashi H, Sasaki Y, Ishikawa M, Lamb DJ, Matsumoto N, Birk OS, Niikawa N, Sengoku K (2006) Polymorphic alleles of the human MEI1 gene are associated with human azoospermia by meiotic arrest. J Hum Genet 51:533–540Google Scholar
  92. Sha YW, Xu X, Mei LB, Li P, Su ZY, He XQ, Li L (2017a) A homozygous CEP135 mutation is associated with multiple morphological abnormalities of the sperm flagella (MMAF). Gene 633:48–53Google Scholar
  93. Sha YW, Wang X, Xu X, Su ZY, Cui Y, Mei LB, Huang XJ, Chen J, He XM, Ji ZY, Bao H, Yang X, Li P, Li L (2017b) Novel mutations in CFAP44 and CFAP43 cause multiple morphological abnormalities of the sperm flagella (MMAF). Reprod Sci 2017:1933719117749756Google Scholar
  94. Sha YW, Wang X, Su ZY, Wang C, Ji ZY, Mei LB, Zhang L, Deng BB, Huang XJ, Yan W, Chen J, Li P, Cui YQ, Qu QL, Yin C, He XM (2018a) TDRD6 is associated with oligoasthenoteratozoospermia by sequencing the patient from a consanguineous family. Gene 659:84–88Google Scholar
  95. Sha YW, Sha YK, Ji ZY, Mei LB, Ding L, Zhang Q, Qiu PP, Lin SB, Wang X, Li P, Xu X, Li L (2018b) TSGA10 is a novel candidate gene associated with acephalic spermatozoa. Clin Genet 93:776–783Google Scholar
  96. Sha Y, Zheng L, Ji Z, Mei L, Ding L, Lin S, Wang X, Yang X, Li P (2018c) A novel TEX11 mutation induces azoospermia: a case report of infertile brothers and literature review. BMC Med Genet 19(1):63Google Scholar
  97. Shannon M, Richardson L, Christian A, Handel MA, Thelen MP (1999) Differential gene expression of mammalian SPO11/TOP6A homologs during meiosis. FEBS Lett 462:329–334Google Scholar
  98. Sironen A, Uimari P, Venhoranta H, Andersson M, Vilkki J (2011) An exonic insertion within Tex14 gene causes spermatogenic arrest in pigs. BMC Genom 12:591Google Scholar
  99. Souquet B, Abby E, Hervé R, Finsterbusch F, Tourpin S, Le Bouffant R, Duquenne C, Messiaen S, Martini E, Bernardino-Sgherri J, Toth A, Habert R, Livera G (2013) MEIOB targets single-strand DNA and is necessary for meiotic recombination. PLoS Genet 9(9):e1003784Google Scholar
  100. Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I (2005a) SYCP3 mutations are uncommon in patients with azoospermia. Fertil Steril 84(4):1019–1020Google Scholar
  101. Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I (2005b) Possible role of USP26 in patients with severely impaired spermatogenesis. Eur J Hum Genet 13:336–340Google Scholar
  102. Sudhakar DVS, Nizamuddin S, Manisha G, Devi JR, Gupta NJ, Chakravarthy BN, Deenadayal M, Singh L, Thangaraj K (2018) NR5A1 mutations are not associated with male infertility in Indian men. Andrologia 50:3Google Scholar
  103. Sun C, Skaletsky H, Birren B, Devon K, Tang Z, Silber S, Oates R, Page DC (1999) An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat Genet 23:429–432Google Scholar
  104. Suzuki H, Ahn HW, Chu T, Bowden W, Gassei K, Orwig K, Rajkovic A (2012) SOHLH1 and SOHLH2 coordinate spermatogonial differentiation. Dev Biol 361:301–312Google Scholar
  105. Tang S, Wang X, Li W, Yang X, Li Z, Liu W, Li C, Zhu Z, Wang L, Wang J, Zhang L, Sun X, Zhi E, Wang H, Li H, Jin L, Luo Y, Wang J, Yang S, Zhang F (2017) Biallelic mutations in CFAP43 and CFAP44 cause male infertility with multiple morphological abnormalities of the sperm flagella. Am J Hum Genet 100:854–864Google Scholar
  106. Tewes AC, Ledig S, Tuttelmann F, Kliesch S (2014) DMRT1 mutations are rarely associated with male infertility. Fertil Steril 102:816–820Google Scholar
  107. Tournaye H, Krausz C, Oates RD (2017) Novel concepts in the aetiology of male reproductive impairment. Lancet Diabetes Endocrinol 5(7):544–553Google Scholar
  108. Tüttelmann F, Ruckert C, Röpke A (2018) Disorders of spermatogenesis: perspectives for novel genetic diagnostics after 20 years of unchanged routine. Med Genet 30(1):2–20Google Scholar
  109. Urh K, Kolenc Ž, Hrovat M, Svet L, Dovč P, Kunej T (2018) Molecular mechanisms of syndromic cryptorchidism: data synthesis of 50 studies and visualization of gene-disease network. Front Endocrinol (Lausanne) 9:425Google Scholar
  110. Vigueras-Villaseñor RM, Cortés-Trujillo L, Chávez-Saldaña M, Vázquez FG, Carrasco-Daza D, Cuevas-Alpuche O, Rojas-Castañeda JC (2015) Analysis of POU5F1, c-Kit, PLAP, AP2γ and SALL4 in gonocytes of patients with cryptorchidism. Acta Histochem 117(8):752–761Google Scholar
  111. Vinci G, Chantot-Bastaraud S, El Houate B et al (2007) Association of deletion 9p, 46,XY gonadal dysgenesis and autistic spectrum disorder. Mol Hum Reprod 13:685–689Google Scholar
  112. Voskarides K (2018) Combination of 247 genome-wide association studies reveals high cancer risk as a result of evolutionary adaptation. Mol Biol Evol 35(2):473–485Google Scholar
  113. Wang X, Jin H, Han F, Cui Y, Chen J, Yang C, Zhu P, Wang W, Jiao G, Wang W, Hao C, Gao Z (2017) Homozygous DNAH1 frameshift mutation causes multiple morphological anomalies of the sperm flagella in. Chin Clin Genet 91:313–321Google Scholar
  114. Wang Y, Gray DR, Robbins AK, Crowgey EL, Chanock SJ, Greene MH, McGlynn KA, Nathanson K, Turnbull C, Wang Z, Devoto M, Barthold JS, Testicular Cancer Consortium (2018) Subphenotype meta-analysis of testicular cancer genome-wide association study data suggests a role for RBFOX family genes in cryptorchidism susceptibility. Hum Reprod 33(5):967–977Google Scholar
  115. Wosnitzer MS, Mielnik A, Dabaja A, Robinson B, Schlegel PN, Paduch DA (2014) Ubiquitin specific protease 26 (USP26) expression analysis in human testicular and extragonadal tissues indicates diverse action of USP26 in cell differentiation and tumorigenesis. PLoS One 9:e98638Google Scholar
  116. Xing H, Wilkerson DC, Mayhew CN, Lubert EJ, Skaggs HS, Goodson ML, Hong Y, Park-Sarge O-K, Sarge KD (2005) Mechanism of hsp70i gene bookmarking. Science 307:421–423Google Scholar
  117. Xu Y, Greenberg RA, Schonbrunn E, Wang PJ (2017) Meiosis-specific proteins MEIOB and SPATA22 cooperatively associate with the single-stranded DNA-binding replication protein A complex and DNA double-strand breaks. Biol Reprod 6(5):1096–1104Google Scholar
  118. Yan W, Si Y, Slaymaker S, Li J, Zheng H, Young DL, Aslanian A, Saunders L, Verdin E, Charo IF (2010) Zmynd15 encodes a histone deacetylase-dependent transcriptional repressor essential for spermiogenesis and male fertility. J Biol Chem 85:31418–31426Google Scholar
  119. Yang F, Eckardt S, Leu NA, McLaughlin KJ, Wang PJ (2008) Mouse TEX15 is essential for DNA double-strand break repair and chromosomal synapsis during male meiosis. J Cell Biol 180(4):673–679Google Scholar
  120. Yatsenko AN, Roy A, Chen R, Ma L, Murthy LJ, Yan W, Lamb DJ, Matzuk MM (2006) Non-invasive genetic diagnosis of male infertility using spermatozoal RNA: KLHL10 mutations in oligozoospermic patients impair homodimerization. Hum Mol Genet 15:3411–3419Google Scholar
  121. Yatsenko AN, Georgiadis AP, Röpke A, Berman AJ, Jaffe T, Olszewska M, Westernströer B, Sanfilippo J, Kurpisz M, Rajkovic A, Yatsenko SA, Kliesch S, Schlatt S, Tüttelmann F (2015) X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med 372(22):2097–2107Google Scholar
  122. Yin H, Ma H, Hussain S, Zhang H, Xie X, Jiang L, Jiang X, Iqbal F, Bukhari I, Jiang H, Ali A, Zhong L et al (2018) A homozygous FANCM frameshift pathogenic variant causes male infertility. Genet Med (Epub ahead of print) Google Scholar
  123. Ying M, Chen B, Tian Y, Hou Y, Li Q, Shang X, Sun J, Cheng H, Zhou R (2007) Nuclear import of human sexual regulator DMRT1 is mediated by importin-beta. Biochim Biophys Acta 1773:804–813Google Scholar
  124. Yuan L, Liu JG, Zhao J, Brundell E, Daneholt B, Hoog C (2000) The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol Cell 5:73–83Google Scholar
  125. Zhu F, Wang F, Yang X, Zhang J, Wu H, Zhang Z, Zhang Z, He X, Zhou P, Wei Z, Gecz J, Cao Y (2016) Biallelic SUN5 mutations cause autosomal-recessive acephalic spermatozoa syndrome. Am J Hum Genet 99:942–949Google Scholar
  126. Živković D, Fratrić I (2014) Disturbances of sperm maturation and minipuberty: is there a connection? Biomed Res Int 2014:912746Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Clinical and Experimental MedicineUniversity of CataniaCataniaItaly

Personalised recommendations