The Genetics of Male Infertility

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

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