The Genetics of Male Infertility

Thomas J. Walsh; Renee Reijo Pera; Paul J. Turek

doi:10.1055/s-0029-1202301

Seminars in Reproductive Medicine, Inhaltsverzeichnis

Semin Reprod Med 2009; 27(2): 124-136
DOI: 10.1055/s-0029-1202301

The Genetics of Male Infertility

Thomas J. Walsh¹ , Renee Reijo Pera² , Paul J. Turek³

¹Department of Urology, University of California - San Francisco, San Francisco, California
²Center for Human Embryonic Stem Cell Research and Education Institute for Stem Cell Biology & Regenerative Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
³The Turek Clinic, San Francisco, California

Abstract

ABSTRACT

Developments in genomic medicine will likely explain much of what is now considered idiopathic male infertility. Indeed, our understanding of the genetic defects that cause infertility is no longer confined to chromosomal aneuploidies (e.g., Klinefelter syndrome) and single-gene defects (cystic fibrosis and congenital absence of the vas deferens). The past decade has seen that isolated Y-chromosomal loci can influence spermatogenesis (AZF regions) and that the human X chromosome is likely to be an important source of spermatogenesis genes. More recently, the finding that faulty recombination occurs in male infertility has large implications not only for the cause of the infertility but also for the use of affected gametes. Indeed, as our understanding of genetic infertility matures, so too will the importance and complexity of genetic counseling and testing for patients who use assisted reproduction.

KEYWORDS

Male infertility - oligospermia - Y chromosome - karyotype - azoospermia

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Referenzen

REFERENCES

1 Palermo G D, Schlegel P N, Sills E S et al.. Births after intracytoplasmic injection of sperm obtained by testicular extraction from men with nonmosaic Klinefelter's syndrome. N Engl J Med. 1998; 338 588-590
2 Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C. Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review. Fertil Steril. 2004; 82 775-779
3 Lowe X, Eskenazi B, Nelson D O et al.. Frequency of XY sperm increases with age in fathers of boys with Klinefelter syndrome. Am J Hum Genet. 2001; 69 1046-1054
4 Jacobs P A, Hassold T J, Whittington E et al.. Klinefelter's syndrome: an analysis of the origin of the additional sex chromosome using molecular probes. Ann Hum Genet. 1988; 52(Pt 2) 93-109
5 Bergere M, Wainer R, Nataf V et al.. Biopsied testis cells of four 47,XXY patients: fluorescence in-situ hybridization and ICSI results. Hum Reprod. 2002; 17 32-37
6 Blanco J, Egozcue J, Vidal F. Meiotic behaviour of the sex chromosomes in three patients with sex chromosome anomalies (47,XXY, mosaic 46,XY/47,XXY and 47,XYY) assessed by fluorescence in-situ hybridization. Hum Reprod. 2001; 16 887-892
7 Shi Q, Martin R H. Aneuploidy in human spermatozoa: FISH analysis in men with constitutional chromosomal abnormalities, and in infertile men. Reproduction. 2001; 121 655-666
8 Gonsalves J, Turek P J, Schlegel P N et al.. Recombination in men with Klinefelter syndrome. Reproduction. 2005; 130 223-229
9 Walzer S, Gerald P S. Social class and frequency of XYY and XXY. Science. 1975; 190 1228-1229
10 Palanduz S, Aktan M, Ozturk S et al.. 47,XYY karyotype in acute myeloid leukemia. Cancer Genet Cytogenet. 1998; 106 76-77
11 Shi Q, Martin R H. Multicolor fluorescence in situ hybridization analysis of meiotic chromosome segregation in a 47,XYY male and a review of the literature. Am J Med Genet. 2000; 93 40-46
12 Wang J Y, Samura O, Zhen D K et al.. Fluorescence in-situ hybridization analysis of chromosomal constitution in spermatozoa from a mosaic 47,XYY/46,XY male. Mol Hum Reprod. 2000; 6 665-668
13 Han T H, Ford J H, Flaherty S P, Webb G C, Matthews C D. A fluorescent in situ hybridization analysis of the chromosome constitution of ejaculated sperm in a 47,XYY male. Clin Genet. 1994; 45 67-70
14 Schweikert H U, Weissbach L, Leyendecker G et al.. Clinical, endocrinological, and cytological characterization of two 46, XX males. J Clin Endocrinol Metab. 1982; 54 745-752
15 Van der Auwera B, Van Roy N, De Paepe A et al.. Molecular cytogenetic analysis of XX males using Y-specific DNA sequences, including SRY. Hum Genet. 1992; 89 23-28
16 Wegner H E, Klan R, Wegner R D et al.. Mixed gonadal dysgenesis associated with unilateral cavernosal fibrosis and presenting as a cystic lower abdominal mass. Eur Urol. 1993; 24 428-430
17 Eriksson A, Tohonen V, Wedell A, Nordqvist K. Isolation of the human testatin gene and analysis in patients with abnormal gonadal development. Mol Hum Reprod. 2002; 8 8-15
18 Rajender S, Thangaraj K, Gupta N J et al.. A novel human sex-determining gene linked to Xp11.21–11.23. J Clin Endocrinol Metab. 2006; 91 4028-4036
19 Van Assche E, Bonduelle M, Tournaye H et al.. Cytogenetics of infertile men. Hum Reprod. 1996; 11(Suppl 4) 1-24 discussion 25-26
20 Tiepolo L, Zuffardi O. Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet. 1976; 34 119-124
21 Vogt P H, Edelmann A, Kirsch S et al.. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet. 1996; 5 933-943
22 Reijo R, Alagappan R K, Patrizio P, Page D C. Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet. 1996; 347 1290-1293
23 Kostiner D R, Turek P J, Reijo R A. Male infertility: analysis of the markers and genes on the human Y chromosome. Hum Reprod. 1998; 13 3032-3038
24 Kleiman S E, Bar-Shira Maymon B, Yogev L, Paz G, Yavetz H. The prognostic role of the extent of Y microdeletion on spermatogenesis and maturity of Sertoli cells. Hum Reprod. 2001; 16 399-402
25 Sun C, Skaletsky H, Birren B et al.. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat Genet. 1999; 23 429-432
26 Foresta C, Moro E, Ferlin A. Prognostic value of Y deletion analysis. The role of current methods. Hum Reprod. 2001; 16 1543-1547
27 Ferlin A, Moro E, Onisto M et al.. Absence of testicular DAZ gene expression in idiopathic severe testiculopathies. Hum Reprod. 1999; 14 2286-2292
28 Hopps C V, Mielnik A, Goldstein M et al.. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod. 2003; 18 1660-1665
29 Krausz C, Bussani-Mastellone C, Granchi S et al.. Screening for microdeletions of Y chromosome genes in patients undergoing intracytoplasmic sperm injection. Hum Reprod. 1999; 14 1717-1721
30 Turek P J, Ljung B M, Cha I, Conaghan J. Diagnostic findings from testis fine needle aspiration mapping in obstructed and nonobstructed azoospermic men. J Urol. 2000; 163 1709-1716
31 van Golde R J, van der Avoort I A, Tuerlings J H et al.. Phenotypic characteristics of male subfertility and its familial occurrence. J Androl. 2004; 25 819-823
32 Choi J M, Chung P, Veeck L et al.. AZF microdeletions of the Y chromosome and in vitro fertilization outcome. Fertil Steril. 2004; 81 337-341
33 Kihaile P E, Kisanga R E, Aoki K et al.. Embryo outcome in Y-chromosome microdeleted infertile males after ICSI. Mol Reprod Dev. 2004; 68 176-181
34 Oates R D, Silber S, Brown L G, Page D C. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod. 2002; 17 2813-2824
35 Mulhall J P, Reijo R, Alagappan R et al.. Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection. Hum Reprod. 1997; 12 503-508
36 Simoni M, Gromoll J, Dworniczak B et al.. Screening for deletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in azoospermia and severe oligozoospermia. Fertil Steril. 1997; 67 542-547
37 Cantu J M, Diaz M, Moller M et al.. Azoospermia and duplication 3qter as distinct consequences of a familial t(X;3) (q26;q13.2). Am J Med Genet. 1985; 20 677-684
38 Madan K. Balanced structural changes involving the human X: effect on sexual phenotype. Hum Genet. 1983; 63 216-221
39 Mattei M G, Mattei J F, Ayme S, Giraud F. X-autosome translocations: cytogenetic characteristics and their consequences. Hum Genet. 1982; 61 295-309
40 Nemeth A H, Gallen I W, Crocker M, Levy E, Maher E. Klinefelter-like phenotype and primary infertility in a male with a paracentric Xq inversion. J Med Genet. 2002; 39 E28
41 Lee S, Lee S H, Chung T G et al.. Molecular and cytogenetic characterization of two azoospermic patients with X-autosome translocation. J Assist Reprod Genet. 2003; 20 385-389
42 Wang P J, McCarrey J R, Yang F, Page D C. An abundance of X-linked genes expressed in spermatogonia. Nat Genet. 2001; 27 422-426
43 Raverot G, Lejeune H, Kotlar T, Pugeat M, Jameson J L. X-linked sex-determining region Y box 3 (SOX3) gene mutations are uncommon in men with idiopathic oligoazoospermic infertility. J Clin Endocrinol Metab. 2004; 89 4146-4148
44 Olesen C, Silber J, Eiberg H et al.. Mutational analysis of the human FATE gene in 144 infertile men. Hum Genet. 2003; 113 195-201
45 Schneider-Gadicke A, Beer-Romero P, Brown L G et al.. Putative transcription activator with alternative isoforms encoded by human ZFX gene. Nature. 1989; 342 708-711
46 Luoh S W, Bain P A, Polakiewicz R D et al.. Zfx mutation results in small animal size and reduced germ cell number in male and female mice. Development. 1997; 124 2275-2284
47 Buchter D, Behre H M, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol. 1998; 139 298-303
48 Bhasin S, Ma K, Sinha I et al.. The genetic basis of male infertility. Endocrinol Metab Clin North Am. 1998; 27 783-805 , viii
49 Layman L C, Cohen D P, Jin M et al.. Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet. 1998; 18 14-15
50 Bick D, Franco B, Sherins R J et al.. Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome. N Engl J Med. 1992; 326 1752-1755
51 Guo W, Burris T P, McCabe E R. Expression of DAX-1, the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism, in the hypothalamic-pituitary-adrenal/gonadal axis. Biochem Mol Med. 1995; 56 8-13
52 Jackson R S, Creemers J W, Ohagi S et al.. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997; 16 303-306
53 Dode C, Levilliers J, Dupont J M et al.. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. 2003; 33 463-465
54 Oliveira L M, Seminara S B, Beranova M et al.. The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab. 2001; 86 1532-1538
55 Jager R J, Anvret M, Hall K, Scherer G. A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature. 1990; 348 452-454
56 Mittwoch U. Sex determination and sex reversal: genotype, phenotype, dogma and semantics. Hum Genet. 1992; 89 467-479
57 Berta P, Hawkins J R, Sinclair A H et al.. Genetic evidence equating SRY and the testis-determining factor. Nature. 1990; 348 448-450
58 Sinclair A H, Berta P, Palmer M S et al.. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990; 346 240-244
59 Yu R N, Ito M, Saunders T L, Camper S A, Jameson J L. Role of Ahch in gonadal development and gametogenesis. Nat Genet. 1998; 20 353-357
60 Ottolenghi C, Pelosi E, Tran J et al.. Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Hum Mol Genet. 2007; 16 2795-2804
61 Mak V, Jarvi K A. The genetics of male infertility. J Urol. 1996; 156 1245-1256 discussion 1256-1247
62 Kerem B, Rommens J M, Buchanan J A et al.. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989; 245 1073-1080
63 Danziger K L, Black L D, Keiles S B, Kammesheidt A, Turek P J. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004; 19 540-546
64 Kupker W, Schwinger E, Hiort O et al.. Genetics of male subfertility: consequences for the clinical work-up. Hum Reprod. 1999; 14(Suppl 1) 24-37
65 Jequier A M, Ansell I D, Bullimore N J. Congenital absence of the vasa deferentia presenting with infertility. J Androl. 1985; 6 15-19
66 Stuhrmann M, Dork T, Fruhwirth M et al.. Detection of 100% of the CFTR mutations in 63 CF families from Tyrol. Clin Genet. 1997; 52 240-246
67 Xu W M, Shi Q X, Chen W Y et al.. Cystic fibrosis transmembrane conductance regulator is vital to sperm fertilizing capacity and male fertility. Proc Natl Acad Sci U S A. 2007; 104 9816-9821
68 Donat R, McNeill A S, Fitzpatrick D R, Hargreave T B. The incidence of cystic fibrosis gene mutations in patients with congenital bilateral absence of the vas deferens in Scotland. Br J Urol. 1997; 79 74-77
69 Phillipson G T, Petrucco O M, Matthews C D. Congenital bilateral absence of the vas deferens, cystic fibrosis mutation analysis and intracytoplasmic sperm injection. Hum Reprod. 2000; 15 431-435
70 Castellani C, Bonizzato A, Pradal U et al.. Evidence of mild respiratory disease in men with congenital absence of the vas deferens. Respir Med. 1999; 93 869-875
71 Noone P G, Knowles M R. 'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations. Respir Res. 2001; 2 328-332
72 Kiesewetter S, Macek Jr M, Davis C et al.. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet. 1993; 5 274-278
73 Chu C S, Trapnell B C, Curristin S, Cutting G R, Crystal R G. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet. 1993; 3 151-156
74 Mickle J, Milunsky A, Amos J A, Oates R D. Congenital unilateral absence of the vas deferens: a heterogeneous disorder with two distinct subpopulations based upon aetiology and mutational status of the cystic fibrosis gene. Hum Reprod. 1995; 10 1728-1735
75 McCallum T, Milunsky J, Munarriz R et al.. Unilateral renal agenesis associated with congenital bilateral absence of the vas deferens: phenotypic findings and genetic considerations. Hum Reprod. 2001; 16 282-288
76 Jarvi K, Zielenski J, Wilschanski M et al.. Cystic fibrosis transmembrane conductance regulator and obstructive azoospermia. Lancet. 1995; 345 1578
77 Shkolny D L, Beitel L K, Ginsberg J et al.. Discordant measures of androgen-binding kinetics in two mutant androgen receptors causing mild or partial androgen insensitivity, respectively. J Clin Endocrinol Metab. 1999; 84 805-810
78 Aiman J, Griffin J E, Gazak J M, Wilson J D, MacDonald P C. Androgen insensitivity as a cause of infertility in otherwise normal men. N Engl J Med. 1979; 300 223-227
79 Yong E L, Ng S C, Roy A C, Yun G, Ratnam S S. Pregnancy after hormonal correction of severe spermatogenic defect due to mutation in androgen receptor gene. Lancet. 1994; 344 826-827
80 Cohen-Haguenauer O, Picard J Y, Mattei M G et al.. Mapping of the gene for anti-mullerian hormone to the short arm of human chromosome 19. Cytogenet Cell Genet. 1987; 44 2-6
81 Imbeaud S, Carre-Eusebe D, Rey R et al.. Molecular genetics of the persistent mullerian duct syndrome: a study of 19 families. Hum Mol Genet. 1994; 3 125-131
82 Imbeaud S, Faure E, Lamarre I et al.. Insensitivity to anti-mullerian hormone due to a mutation in the human anti-mullerian hormone receptor. Nat Genet. 1995; 11 382-388
83 Zimmermann S, Steding G, Emmen J M et al.. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol. 1999; 13 681-691
84 Tomboc M, Lee P A, Mitwally M F et al.. Insulin-like 3/relaxin-like factor gene mutations are associated with cryptorchidism. J Clin Endocrinol Metab. 2000; 85 4013-4018
85 Baker S M, Bronner C E, Zhang L et al.. Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Cell. 1995; 82 309-319
86 Nudell D, Castillo M, Turek P J, Pera R R. Increased frequency of mutations in DNA from infertile men with meiotic arrest. Hum Reprod. 2000; 15 1289-1294
87 Maduro M R, Casella R, Kim E et al.. Microsatellite instability and defects in mismatch repair proteins: a new aetiology for Sertoli cell-only syndrome. Mol Hum Reprod. 2003; 9 61-68
88 Coop G, Przeworski M. An evolutionary view of human recombination. Natl Rev. 2007; 8 23-34
89 Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Natl Rev. 2001; 2 280-291
90 Baker S M, Plug A W, Prolla T A et al.. Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nat Genet. 1996; 13 336-342
91 Lynn A, Koehler K E, Judis L et al.. Covariation of synaptonemal complex length and mammalian meiotic exchange rates. Science. 2002; 296 2222-2225
92 Marcon E, Moens P. MLH1p and MLH3p localize to precociously induced chiasmata of okadaic-acid-treated mouse spermatocytes. Genetics. 2003; 165 2283-2287
93 Judis L, Chan E R, Schwartz S, Seftel A, Hassold T. Meiosis I arrest and azoospermia in an infertile male explained by failure of formation of a component of the synaptonemal complex. Fertil Steril. 2004; 81 205-209
94 Gonsalves J, Sun F, Schlegel P N et al.. Defective recombination in infertile men. Hum Mol Genet. 2004; 13 2875-2883
95 Topping D, Brown P, Judis L et al.. Synaptic defects at meiosis I and non-obstructive azoospermia. Hum Reprod. 2006; 21 3171-3177
96 Sun F, Greene C, Turek P J et al.. Immunofluorescent synaptonemal complex analysis in azoospermic men. Cytogenet Genome Res. 2005; 111 366-370
97 Sun F, Oliver-Bonet M, Liehr T et al.. Analysis of non-crossover bivalents in pachytene cells from 10 normal men. Hum Reprod. 2006; 21 2335-2339
98 Sun F, Oliver-Bonet M, Liehr T et al.. Variation in MLH1 distribution in recombination maps for individual chromosomes from human males. Hum Mol Genet. 2006; 15 2376-2391
99 Kaplan K D, Brown M, Croughan M S, Turek P J. The relative accuracy of a questionnaire compared with pedigree analysis in genetic risk assessment for infertility. J Urol. 2008; 179 1499-1505

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