Progress in Genetic Factors for Male Infertility

doi:10.3969/j.issn.2095-1396.2016.05.008

Abstract

Abstract: Male infertility was caused by mutiple factors，including both genetic and environmental factors. Nearly 50% of clinic male infertility disorders were from genetic defects，which had shown mainly four different variation hierarchies，aneuploid chromosome variation，structural chromosome variation，gene copy number variation and single gene mutation. In recent years the increasingly deep recognition of genetic male infertility has been witnessed. This review summarizes the research progress of the genetic factors for male infertility on the aspects of epidemiology，mechanisms and pathological changes，from aforesaid four different variations.

Key words: male infertility, genetic defect, chromosome variation, gene copy number variation, single gene mutation

CHEN Wen-yang, SHEN Li-xia, ZHANG Gui-rong. Progress in Genetic Factors for Male Infertility[J]. ACTA NEUROPHARMACOLOGICA, 2016, 6(5): 53-64.

References

1 World Health Organisation Press. Who manual for the standardised investigation and diagnosis of the infertile couple[S]. 2000.

2 Andreas Jungwirth, Aleksander Giwercman, Herman Tournaye, et al. European association of urology guidelines on male infertility: the 2012 update[J]. Eur Urol, 2012, 62(2): 324-332.

3 Michelle Zorrilla, Alexander N Yatsenko. The genetics of infertility: current status of the field[J]. Curr Genet Med Rep, 2013, 1(4): 1-22.

4 Gary L Harton, Helen G Tempest. Chromosomal disorders and male infertility[J]. Asian J Androl, 2012, 14(1): 32-39.

5 Csilla Krausz, Claudia Giachini, Deborah Lo Giacco, et al. High resolution x chromosome-specific array-cgh detects new cnvs in infertile males[J]. PLoS One, 2012, 7(10): 1-13.

6 Pienkowski C, Cartault A, Caula-Legriel S, et al. Klinefelter's syndrome and turner's syndrome. for a better management[J]. Gynecol Obstet Fertil, 2011, 39(9): 521-524.

7 Sophie Van Rijn, Hanna Swaab, Andre Aleman, et al. Social behavior and autism traits in a sex chromosomal disorder: klinefelter (47xxy) syndrome[J]. J Autism Dev Disord, 2008, 38(9): 1634-1641.

8 Mao Jiang-Feng, Xu Hong-Li, Wu Xue-Yan, et al. Prevalence and risk factors of diabetes in patients with klinefelter syndrome: a longitudinal observational study[J]. Fertil Steril, 2012, 98(5): 1331-1335.

9 Nobuhito Sasaki, Kohei Yamauchi, Ryo Sato, et al. Klinefelter's syndrome associated with systemic lupus erythematosus and autoimmune hepatitis[J]. Mod Rheumatol, 2006, 16(5): 305-308.

10 Abdul Rehman, Zubair Hasan, Samina Amanat, et al. Combined persistent mullerian duct syndrome, transverse testicular ectopia and mosaic klinefelter's syndrome[J]. J Coll Physicians Surg Pak, 2008, 18(6): 375-377.

11 Anu Rita Jayaraman, Maithreyi Poguri, Nambi Siva. A case report of klinefelter syndrome with schizophrenia-like psychosis and seizure disorder[J]. Indian J Psychol Med, 2015, 37 (3), 364-365.

12 Robert D Oates. The natural history of endocrine function and spermatogenesis in klinefelter syndrome:what the data show[J]. Fertil Steril, 2012, 98(2): 266-273.

13 Hanane Latrech, Imane Skikar, Mohammed El Hassan Gharbi, et al. Disorder of sexual development and congenital heart defect in47xyy: clinical disorder or coincidence?[J]. Case Rep Endocrinol, 2015, 2015:1-5.

14 Martin R H. Cytogenetic determinants of male fertility[J]. Hum Reprod Update, 2008, 14 (4): 379–390.

15 Michelle Zorrilla, Alexander N Yatsenko. The genetics of infertility: current status of the field[J]. Curr Genet Med Rep, 2013, 1(4): 1-22.

16 Rajesh Shankar Iyer, Thanikasalam, Mugundhan Krishnan. Migrating partial seizures in infancy and 47xyy syndrome: cause or coincidence?[J]. Epilepsy Behav Case Rep, 2014, 2: 43-45.

17 Katherine L O'Flynn O'Brien, Alex C Varghese, Ashok Agarwal. The genetic causes of male factor infertility: a review[J]. Fertil Steril, 2010, 93 (1): 1-12.

18 Jiang Han-wei, Wang Liu, Cui Ying-xia, et al. Meiotic chromosome behavior in a human male t(8;15) carrier[J]. J Genet Genomics, 2014, 41 (3): 177-185.

19 Kavita Shalender, Gayathri Sivapalan, Nicola Gibbons, et al. The genetic basis of infertility[J]. Reproduction, 2003, 126, 13-25.

20 Thejaswini Venkatesh, Padmanaban S Suresh, Rie Tsutsumi. New insights into the genetic basis of infertility[J]. Appl Clin Genet, 2014, 7: 235-243.

21 Carolina Goncalves, Mariana Cunha, Eduardo Rocha, et al. Y-Chromosome microdeletions in nonobstructive azoospermia and severe oligozoospermia[J]. Asian J Androl, 2016, 19(3): 338-345.

22 X G Liu, H Y Hu, Y H Guo, et al. Correlation between y chromosome microdeletion and male infertility[J]. Genet. Mol, 2016, 15 (2): 1-8.

23 Krausz C, Casamonti E. Spermatogenic failure and the y chromosome[J]. Hum Genet, 2017, 136(5): 637-655.

24 Liu XG, Hu HY, Guo YH, et al. Correlation between y chromosome microdeletion and male infertility[J]. Genet Mol Res, 2016, 15 (2), 1-8.

25 P H Vogt, A Edelmann, Stefan Kirsch, et al. Human Y chromosome azoospermia factors (azf) mapped to different subregions in yq11[J]. Hum Mol Genet, 1996, 5: 933-943.

26 Suganthi R, Vijesh VV, Vandana N, et al. Y Choromosomal microdeletion screening in the workup of male infertility and its current status in india[J]. Int J Fertil Steril, 2014, 7, 253-266.

27 Yu Xiao-Wei, Wei Zhen-Tong, Jiang Yu-Ting, et al. Y chromosome azoospermia factor region microdeletions and transmission characteristics in azoospermic and severe oligozoospermic patients[J]. Int J Clin Exp Med, 2015, 8(9): 14634-14646.

28 Angel Gallego, Ramon Rogel, Saturnino Luján, et al. Azf gene microdeletions: case series and literature review[J]. Actas Urol Esp, 2014, 38(10): 698-702.

29 Kazumasa Komura, Seong Ho Jeong, Kunihiko Hinohara, et al. Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of kdm5d expression [J]. Proc Natl Acad Sci USA, 2016, 113(22): 6259-6264.

30 Alexandra M Lopes, Ricardo N Miguel, Carole A Sargent, et al. The human rps4 paralogue on yq11.223 encodes a structurally conserved ribosomalprotein and is preferentially expressed during spermatogenesis[J]. BMC Mol Biol, 2010, 7, 11-33.

31 Fernando L Mendez, G David Poznik, Sergi Castellano, et al. The divergence of neandertal and modern human y chromosomes[J]. Am J Hum Genet, 2016, 98(4): 728-734.

32 Dai R L, Hou Y, Li F B, et al. Varicocele and male infertility in northeast china: y chromosome microdeletion as an underlying cause[J]. Genet Mol Res, 2015, 14(2): 6583-6590.

33 Rodovalho R G, Arruda J T, Moura K K. Tracking microdeletions of the azf region in a patrilineal line of infertile men[J]. Genet Mol Res, 2008, 7(3): 614-622.

34 Fu Xia-fei, Cheng Shun-feng, Wang Lin-qing, et al. Daz family proteins, key players for germ cell development[J]. Int J Biol Sci, 2015, 11(10): 1226-1235.

35 Yu XW, Wei ZT, Jiang YT, et al. Y chromosome azoospermia factor region microdeletions and transmission characteristics in azoospermic and severe oligozoospermic patients.[J]. Int J Clin Exp Med, 2015, 8 (9), 14634-14646.

36 Zhao Wei-wei, Wu Meng-hua, Chen Fan, et al. Robertsonian translocations: an overview of 872 robertsonian translocations identified in a diagnostic laboratory in china[J]. PLoS One, 2015, 10(5): 1-14.

37 Sung-Ryul Kim, Lisa G Shaffer. Robertsonian translocations: mechanisms of formation, aneuploidy, and uniparental disomy and diagnostic considerations[J]. Genet Test, 2002, 6: 163-168.

38 Stephanie Huang, Kara Juneau, Patrick E Bogard, et al. Identifying robertsonian translocation carriers by microarray-based dna analysis[J]. Fetal Diagn Ther, 2016, 40(1): 59-62.

39 Zhuang Xin-jie, Huang Jin, Jin Xiao-hu, et al. Chromosome aberrations and spermatogenic disorders in mice with robertsonian translocation (11; 13)[J]. Int J Clin Exp Pathol, 2014, 7(11): 7735-7743.

40 Moh-Ying Yip. Uniparental disomy in robertsonian translocations: strategies for uniparental disomy testing[J]. Transl Pediatr, 2014, 3(2): 98-107.

41 Tossaporn Seeherunvong, Supamit Ukarapong, Kenneth McElreavey, et al. Duplication of sox9 is not a common cause of 46,xx testicular or 46,xx ovotesticular dsd[J]. J Pediatr Endocrinol Metab, 2012, 25(1-2): 121-123.

42 Juan Carlos Polanco, Dagmar Wilhelm, Tara-Lynne Davidson, et al. Sox10 gain-of-function causes xx sex reversal in mice: implications for human 22q-linked disorders of sex development[J]. Hum Mol Genet, 2010, 19(3): 506-516.

43 Clinton K Matson, David Zarkower. Sex and the singular dm domain: insights into sexual regulation, evolution and plasticity[J]. Nat Rev Genet, 2012, 13(3): 163-174.

44 Anna Biason-Lauber, Marie-Christine Chaboissier. Ovarian development and disease: the known and the unexpected[J]. Semin Cell Dev Biol, 2015, 45: 59-67.

45 Romina P Grinspon, Rodolfo A Rey. Disorders of sex development with testicular differentiation in sry-negative 46,xx individuals: clinical and genetic aspects[J]. Sex Dev, 2016, 10(1): 1-11.

46 Xiao Bing, Ji Xing, Xing Ya, et al. A rare case of 46, xx sry-negative male with approximately 74-kb duplication in a region upstream of sox9[J]. Eur J Med Genet, 2013, 56(12): 695-698.

47 James J Cox, Lionel Willatt, Tessa Homfray, et al. A sox9 duplication and familial 46, xx developmental testicular disorder[J]. N Engl J Med, 2011, 364(1): 91-93.

48 Huang Bing, Wang Sheng-biao, Ning Yi, et al. Autosomal Xx sex reversal caused by duplication of sox9[J]. Am J Med Genet, 1999, 87(4): 349-353.

49 Sabina Benko, Christopher T Gordon, Delphine Mallet, et al. Disruption of a long distance regulatory region upstream of sox9 in isolated disorders of sex development[J]. J Med Genet, 2011, 48(12): 825-830.

50 Annalisa Vetro, Roberto Ciccone, Roberto Giorda, et al. Xx males sry negative: a confirmed cause of infertility[J]. J Med Genet, 2011, 48(10): 710-712.

51 Osama Refai, Andrew Friedman, Lori Terry, et al. De Novo 12;17 Translocation upstream of sox9 resulting in 46,xx testicular disorder of sex development[J]. Am J Med Genet A, 2010, 152A(2): 422-426.

52 Colin E Bishop, Deanne J Whitworth, Qin Yan-jun, et al. A transgenic insertion upstream of sox9 is associated with dominant xx sex reversal in the mouse[J]. Nat Genet, 2000, 26(4): 490-494.

53 Helle Lybæk, Diederik de Bruijn, Anke HA den Engelsman-van Dijk, et al. Revsex duplication-induced and sex-related differences in the sox9 regulatory region chromatin landscape in human fibroblasts[J]. Epigenetics, 2014, 9(3): 416-427.

54 Christa Lese Martin, Brianne E Kirkpatrick, David H Ledbetter. Copy number variants, aneuploidies, and human disease[J]. Clin Perinatol, 2015, 42(2): 227-242.

55 Lorenzo Tattini, Romina D'Aurizio, Alberto Magi. Detection of genomic structural variants from next-generation sequencing data[J]. Front Bioeng Biotechnol, 2015, 3(92): 1-8.

56 Frank Tüttelmann, Manuela Simoni, Sabine Kliesch, et al. Copy number variants in patients with severe oligozoospermia and sertoli-cell-only syndrome[J]. PLoS One, 2011, 6(4): 1-11.

57 Dong Y, Pan Y, Wang R, et al. Copy number variations in spermatogenic failure patients with chromosomal abnormalities and unexplained azoospermia[J]. Genet Mol Res, 2015, 14(4): 19041-19049.

58 Yu Jian-min, Chen Zhang-hui, Ni Ya, et al. Cftr mutations in men with congenital bilateral absence of the vas deferens (cbavd): a systemic review and meta-analysis[J]. Hum Reprod, 2012, 27(1): 25-35.

59 David C Gadsby, Paola Vergani, Laszlo Csanády. The abc protein turned chloride channel whose failure causes cystic fibrosis[J]. Nature, 2006, 440(7083): 477-483.

60 Yang Xiao-jian, Sun Qi-peng, Yuan Ping, et al. Novel mutations and polymorphisms in the cftr gene associated with three subtypes of congenital absence of vas deferens[J]. Fertil Steril, 2015, 104(5): 1268-1275.

61 Marco G Alves, Rosalia Sá, T Tito Jesus, et al. Cftr regulation of aquaporin-mediated water transport: a target in male fertility[J]. Curr Drug Targets, 2015, 16(9): 993-1006.

62 Benjamin Boucherle, Johanna Bertrand, Bruno Maurin, et al. A new 9-alkyladenine-cyclic methylglyoxal diadduct activates wt- and f508del-cystic fibrosis transmembrane conductance regulator (cftr) in vitro and in vivo[J]. Eur J Med Chem, 2014, 83: 455-465.

63 Pascal Jezequel, Christele Dubourg, Dominique Le Lannou, et al. Molecular screening of the cftr gene in men with anomalies of the vas deferens: identification of the three novel mutation[J]. Mol Hum Reprod, 2000, 6(12): 1063-1067.

64 Liborio Stuppia, Ivana Antonucci, Francesco Binni, et al. Screening of mutations in the cftr gene in 1195 couples entering assisted reproduction technique programs[J]. Eur J Hum Genet, 2005, 13: 959–964.

65 Lucia Tamburino, Guglielmino A, Venti E, et al. Molecular analysis of mutations and polymorphisms in the cftr gene in male infertility[J]. Reprod Biomed Online, 2008, 17(1): 27-35.

66 Ni Wu-hua, Jiang Lei, Fei Qian-jin, et al. The cftr polymorphisms poly-t, tg-repeats and m470v in chinese males with congenital bilateral absence of the vas deferens[J]. Asian J Androl, 2012, 14(5): 687-690.

67 Chee Y Ooi, Ruslan Dorfman, Marco Cipolli, et al. Type of cftr mutation determines risk of pancreatitis in patients with cystic fibrosis[J]. Gastroenterology, 2011, 140(1): 153-161.

68 Seiichi Villalona, Guiilermo Glover-López, Juan Antonio Ortega-García, et al. R248g cystic fibrosis transmembrane conductance regulator mutation in three siblings presenting with recurrent acute pancreatitis and reproductive issues: a case series[J]. J Med Case Rep, 2017, 11(1): 42.

69 Himanshu Sharma, Mathilde Jollivet Souchet, Isabelle Callebaut, et al. Function, pharmacological correction and maturation of new indian cftr gene mutations[J]. J Cyst Fibros, 2015, 14(1): 34-41.

70 Justine L Garner, Kirsten M Niles, Serge McGraw, et al. Stability of DNA methylation patterns in mouse spermatogonia under conditions of mthfr deficiency and methionine supplementation[J]. Biol Reprod, 2013, 89(5): 125.

71 Kelly T L, Neaga O R, Schwahn B C, et al. Infertility in 5,10-methylenetetrahydrofolate reductase (mthfr)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation[J]. Biol Reprod, 2005, 73(3): 667-677.

72 Abdelmajid Eloualid, Omar Abidi, Majida Charif, et al. Association of the Mthfr A1298c variant with unexplained severe male infertility[J]. PLoS One, 2012, 7(3): 1-7.

73 Kiran Singh, Deepika Jaiswal. One-Carbon metabolism, spermatogenesis, and male infertility[J]. Reprod Sci, 2013, 20(6): 622-630.

74 Seyedeh Shahrokhi, Faranak Kazerouni, Firouzeh Ghaffari, et al. The relationship between the mthfr c677t genotypes to serum anti-müllerian hormone concentrations and in vitro fertilization/intracytoplasmic sperm injection outcome[J]. Clin Lab, 2017, 63(5): 927-934.

75 Zhang Qiang, Yin Guo-ying, Liu Juan, et al. Association between Mthfr A1298c polymorphism and male infertility: a meta-analysis[J]. J Huazhong Univ Sci Technolog Med Sci, 2017, 37(2): 153-160.

76 Yang Y, Luo YY, Wu S, et al. Association between C677t and A1298c polymorphisms of the mthfr gene and risk of male infertility: a meta-analysis[J]. Genet Mol Res, 2016, 15 (2).

77 Nishi Gupta, Saraswati Gupta, Madhukar Dama, et al. Strong association of 677 c>t substitution in the mthfr gene with male infertility--a study on an indian population and a meta-analysis[J]. PLoS One, 2011, 6(7): 1-14.

78 Zhu Xu-dong, Liu Zhi-guo, Zhang Mao-chen, et al. Association of the methylenetetrahydrofolate reductase gene c677t polymorphism with the risk of male infertility: a meta-analysis[J]. Ren Fail, 2016, 38(2): 185-193.

79 Marcello Machado Gava, Elisangela Chagas, Bianca Bianco, et al. Methylenetetrahydrofolate reductase polymorphisms are related to male infertility in brazilian men[J]. Genet Test Mol Biomarkers, 2011, 15(3): 153-157.

80 Djalila Chellat, Mohamed Larbi Rezgoune, Douadi Hamane, et al. Influence of methylenetetrahydrofolate reductase c677t gene polymorphisms in algerian infertile men with azoospermia or severe oligozoospermia[J]. Genet Test Mol Biomarkers, 2012, 16(8): 874-878.

81 Nishi Gupta, Saumya Sarkar, Archana David, et al. Significant impact of the mthfr polymorphisms and haplotypes on male infertility risk[J]. PLoS One, 2013, 8(7): 1-13.

82 Karimian M, Hosseinzadeh Colagar A. Human Mthfr-G1793a transition may be a protective mutation against male infertility: a genetic association study and in silico analysis[J]. Hum Fertil (Camb), 2017, 7: 1-9.

83 Liu Gang, Lu Guang-xiu, Xing Xiao-wei. Molecular cloning of tsarg6 gene related to apoptosis in human spermatogenic cells[J]. Acta Biochim Biophys Sin, 2004, 36(2): 93-98.

84 Li Wei-na, Liu Gang. Dnajb13, a Type Ii Hsp40 family member, localizes to the spermatids and spermatozoa during mouse spermatogenesis[J]. BMC Dev Biol, 2014, 14(38): 1-7.

85 Guan Ji-kui, Yuan Li. A Heat-Shock protein 40, dnajb13, is an axoneme-associated component in mouse spermatozoa[J]. Mol Reprod Dev, 2008, 75: 1379-1386.

86 Asami Oji, Taichi Noda, Yoshitaka Fujihara, et al. Crispr/Cas9 mediated genome editing in es cells and its application for chimeric analysis in mice[J]. Sci Rep, 2016, 2016: 1-9.

87 El Khouri Elma, Thomas Lucie, Jeanson Ludovic, et al. Mutations in dnajb13, encoding an hsp40 family member, cause primary ciliary dyskinesia and male infertility[J]. Am J Hum Genet, 2016, 99(2): 489-500.

88 杨梦月, 熊紫薇, 李维娜, 等. 小鼠dnajb13与hk1的相互作用[J]. 南医科大学学报, 2016, 36(12): 1684-1688.

89 Wang Xiao-na, Li Ze-song, Ren Yu, et al. The wilms tumor gene, wt1, is critical for mouse spermatogenesis via regulation of sertoli cell polarity and is associated with non-obstructive azoospermia in humans[J]. PLoS Genet, 2013, 9(8): 1-12.

90 Chen Su-ren, Chen Min, Wang Xiao-na, et al. The wilms tumor gene, wt1, maintains testicular cord integrity by regulating the expression of col4a1 and col4a2[J]. Biol Reprod, 2013, 88(3): 56.

91 Chen Wei-shen, Dragana Antic, Maja Matis, et al. Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling[J]. Cell, 2008, 133(6): 1093-1105.

92 Gao Fei, Sourindra Maiti, Nargis Alam, et al. The wilms tumor gene, wt1, is required for sox9 expression and maintenance of tubular architecture in the developing testis[J]. Proc Natl Acad Sci USA, 2006, 103: 11987-11992.

93 Catarina M Seabra, Sofia Quental, Ana Cristina Cunha Figueiredo Lima, et al. The mutational spectrum of wt1 in male infertility[J]. J Urol, 2015, 193: 1709-1715.

94 Xu Jin, Jiang Li-le, Yu Wen-zhu, et al. A novel functional variant in wilms' tumor 1 (wt1) is associated with idiopathic non-obstructive azoospermia[J]. Mol Reprod Dev, 2017, 84(3): 222-228.

95 Peter J Romanienko, R Daniel Camerini-Otero. Cloning, characterization, and localization of mouse and human spo11[J]. Genomics, 1999, 61: 156-169.

96 Greg L Christensen, Ivaylo P Ivanov, John F Atkins, et al. Screening the spo11 and eif5a2 genes in a population of infertile men[J]. Fertility Sterility, 2005, 84: 758-760.

97 Isabel Lam, Scott Keeney. Mechanism and regulation of meiotic recombination initiation[J]. Cold Spring Harb Perspect Biol, 2015, 7: 1-24.

98 Scott Keeney. Spo11 and the formation of dna doublestrand breaks in meiosis[J]. Genome Dyn Stab, 2008, 2: 81-123.

99 Faieta M, Di Cecca S, de Rooij D G, et al. A surge of late-occurring meiotic double-strand breaks rescues synapsis abnormalities in spermatocytes of mice with hypomorphic expression of spo11[J]. Chromosoma, 2016, 125: 189-203.

100 Frederic Baudat, Katia Manova, Julie Pui Yuen, et al. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking spo11[J]. Mol Cell, 2000, 6(5): 989-998.

101 Natalya A Smirnova, Peter J Romanienko, Pavel P Khil, et al. Gene expression profiles of spo11-/- mouse testes with spermatocytes arrested in meiotic prophase i.gene expression profiles of spo11-/- mouse testes with spermatocytes arrested in meiotic prophase i[J]. Reproduction, 2006, 132, 67-77.

102 Zhang Jing, Zhou Dang-xia, Wang Hai-wu, et al. An association study of spo11 gene single nucleotide polymorphisms with idiopathic male infertility in chinese han population[J]. J Assist Reprod Genet, 2011, 28(8): 731-736.

103 Ren Zheng-ju, Ren Peng-wei, Yang Bo, et al. The spo11-c631t gene polymorphism and male infertility risk: a meta-analysis[J]. Ren Fail, 2017, 39(1): 299-305.

104 Mohammad Karimian, Hossein Nikzad, Abolfazl Azami-Tameh, et al. Spo11-C631t gene polymorphism: association with male infertility and an in silico-analysis[J]. J Family Reprod Health, 2015, 9(4): 155-163.

105 Shi Yong-yong, He Lin. Shesis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci[J]. Cell Res, 2005, 15(2): 97-98.

106 Laila Imken, Hassan Rouba, Brahim EI Houate, et al. Mutations in the protamine locus: association with spermatogenic failure? [J]. Mol Hum Reprod, 2009, 15: 733-738.

107 Rafael Oliva. Protamines and male infertility[J]. Hum Reprod Update, 2006, 12: 417-435.

108 Rod Balhorn. The protamine family of sperm nuclear proteins[J]. Genome Biol, 2007, 8(9): 227.

109 Barbara Luke, Morton B Brown, Ethan Wantman. Cumulative birth rates with linked assisted reproductive technology cycles[J]. N Engl J Med, 2012, 366: 2483-2491.

110 Chunghee Cho, Haesook Jung-Ha, William D Willis, et al. Protamine 2 deficiency leads to sperm dna damage and embryo death in mice[J]. Reprod Biomed Online, 2003, 69(1): 211-217.

111 Luke Simon, Judit Castillo, Rafael Oliva. Relationships between human sperm protamines, dna damage and assisted reproduction outcomes[J]. Reprod Biomed Online, 2011, 23: 724-734.

112 Yu Qing-feng, Yang Xue-xi, Li Fen-xia, et al. Association of prm1-190c-> a polymorphism with teratozoospermia[J]. Zhonghua Nan Ke Xue, 2012, 18: 314-317.

113 Cristina Gazquez, Josep Oriola, Sara de Mateo Lopez, et al. A Common protamine 1 promoter polymorphism (-190 c -> a) correlates with abnormal sperm morphology and increased protamine p1/p2 ratio in infertile patients[J]. J. Androl, 2008, 29: 540-548.

114 Sahar Moghbelinejad, Reza Najafipour, Amir Samimi Hashjin. Comparison of protamine 1 to protamine 2 mrna ratio and ybx2 gene mrna content in testicular tissue of fertile and azoospermic men[J]. Int J Fertil Steril, 2015, 9(3): 338-345.

115 Jiang Wei-jun, Sun Hui, Zhang Jing, et al. Polymorphisms in protamine 1 and protamine 2 predict the risk of male infertility: a meta-analysis[J]. Sci Rep, 2015, 5: 1-11.

116 Nigel C Bennett, Robert A Gardiner, John D Hooper, et al. Molecular cell biology of androgen receptor signalling[J]. Int J Biochem Cell Biol, 2010, 42: 813-827.

117 William H Walker. Non-Classical actions of testosterone and spermatogenesis[J]. Philos Trans R Soc Lond B Biol Sci, 2010, 365(1546): 1557-1569.

118 Laura O'Hara, Lee B Smith. Androgen receptor roles in spermatogenesis and infertility[J]. Best Pract Res Clin Endocrinol Metab, 2015, 29(4): 595-605.

119 Pan Bi-hui, Li Rui, Chen Yao, et al. Genetic association between androgen receptor gene cag repeat length polymorphism and male infertility: a meta-analysis[J]. Medicine (Baltimore), 2016, 95(10): 1-10.

120 Guido Verhoeven, Ariane Willems, Evi Denolet, et al. Androgens and spermatogenesis: lessons from transgenic mouse models[J]. Philos Trans R Soc Lond B Biol Sci, 2010, 365(1546): 1537-1556.

121 Elias ElInati, Camille Fossard, Ozlem Okutman, et al. A new mutation identified in spata16 in two globozoospermic patients[J]. J Assist Reprod Genet, 2016, 33(6), 815-820.

122 Anika H D M Dam, Isabelle Koscinski, Jan A M Kremer, et al. Homozygous mutation in spata16 is associated with male infertility in human globozoospermia[J]. Am J Hum Genet, 2007, 81(4): 813-820.

123 Aminata Touré, Pierre Lhuillier, Jan A Gossen, et al. The testis anion transporter 1 (slc26a8) is required for sperm terminal differentiation and male fertility in the mouse[J]. Hum Mol Genet, 2007, 16(15): 1783-1793.

124 Thassadite Dirami, Baptiste Rode, Mathilde Jollivet, et al. Missense mutations in slc26a8, encoding a sperm-specific activator of cftr, are associated with human asthenozoospermia[J]. Am J Hum Genet, 2013, 92 (5), 760-766.

125 Chieh-Ju C Tang, Lin Chun-yi, Tang K Tang. Dynamic localization and functional implications of aurora-c kinase during male mouse meiosis[J]. Dev Biol, 2006, 290(2): 398-410.

126 Sarah Kimmins, Claudia Crosio, Noora Kotaja, et al. Differential functions of the aurora-b and aurora-c kinases in mammalian spermatogenesis[J]. Mol Endocrinol, 2007, 21(3): 726-739.

127 Leyla Ounis, Abdelali Zoghmar, Charles Coutton, et al. Mutations of the aurora kinase c gene causing macrozoospermia are the most frequent genetic cause of male infertility in algerian men[J]. Asian J Androl, 2015, 17(1): 68-73.

128 Klaus Dieterich, Raoudha Zouari, Radu Harbuz, et al. The aurora kinase c c.144delc mutation causes meiosis i arrest in men and is frequent in the north african population[J]. Hum Mol Genet, 2009, 18(7): 1301-1309.

129 Houda Ghédir, Moez Gribaa, Ons Mamaî, et al. Macrozoospermia: screening for the homozygous c.144delc mutation in aurkc gene in infertile men and estimation of its heterozygosity frequency in the tunisian population[J]. J Assist Reprod Genet, 2015, 32(11): 1651-1658.

130 Suzanne M Quartuccio, Karen Schindler. Functions of aurora kinase c in meiosis and cancer[J]. Front Cell Dev Biol, 2015, 3: 1-8.

131 Yan Wei, Ma Lang, Kathleen H Burns, et al. Haploinsufficiency of kelch-like protein homolog 10 causes infertility in male mice[J]. Proc Natl Acad Sci USA, 2004, 101(20): 7793-7798.

132 Toshinobu Miyamoto, Gaku Minase, Kimika Okabe, et al. Male infertility and its genetic causes[J]. J Obstet Gynaecol Res, 2015, 41(10): 1501-1505.

133 Alexander N Yatsenko, Angshumoy Roy, Chen Rui-hong, et al. Non-Invasive genetic diagnosis of male infertility using spermatozoal rna: klhl10 mutations in oligozoospermic patients impair homodimerization[J]. Hum Mol Genet, 2006, 15(23): 3411-3419.

134 Ferlin A, Raicu F, Gatta V, et al. Male infertility: role of genetic background[J]. Reprod Biomed Online, 2007, 14 (6), 734-745.

135 Martin M Matzuk, Dolores J Lamb. The biology of infertility: research advances and clinical challenges[J]. Nat Med, 2008, 14(11): 1197-1213.