Spermatogenic Failure 1

Description

Spermatogenic arrest during meiosis is a cause of infertility. The histologic picture of meiotic arrest is rather constant. Meiotic arrest is characterized by germ cells that enter meiosis and undergo the first chromosomal reduction from 4n to 2n but are then unable to proceed further. This results in tubules containing spermatocytes as the latest developmental stage of germ cells. Meiotically arrested spermatocytes accumulate in the tubules, degenerate, and are easily distinguishable from normal spermatocytes by their partially condensed chromosomes. Although the cause of infertility in patients with meiotic arrest often remains unidentified, this histologic picture can be observed in patients with nonidiopathic infertility as well, such as in the case of microdeletions of the Y chromosome, chromosomal abnormalities, and cryptorchidism, suggesting that different causal factors can result in the same effect (summary by Luetjens et al., 2004).

Genetic Heterogeneity of Spermatogenic Failure

SPGF1 represents an autosomal recessive form of spermatogenic failure associated with defects in meiosis. Also see SPGF2 (108420), associated with rearrangements on chromosome 1; SPGF3 (606766), caused by mutation in the SLC26A8 gene (608480) on chromosome 6p21; SPGF4 (270960), caused by mutation in the SYCP3 gene (604759) on chromosome 12q23; SPGF5 (243060), caused by mutation in the AURKC gene (603495) on chromosome 19q13; SPGF6 (102530), caused by mutation in the SPATA16 gene (609856) on chromosome 3q26; SPGF7 (612997), caused by mutation in the CATSPER gene (606389) on chromosome 11q13; SPGF8 (613957), caused by mutation in the NR5A1 gene (184757) on chromosome 9q33; SPGF9 (613958), caused by mutation in the DPY19L2 gene (613893) on chromosome 12q14; SPGF10 (614822), caused by mutation in the SEPT12 gene (611562) on chromosome 16p13; SPGF11 (615081), caused by mutation in the KLHL10 gene (608778) on chromosome 17p21; SPGF12 (615413), caused by mutation in the NANOS1 gene (608226) on chromosome 10q26; SPGF13 (615841), caused by mutation in the TAF4B gene (601689) on chromosome 18q11; SPGF14 (615842), caused by mutation in the ZMYND15 gene (614312) on chromosome 17p13; SPGF15 (616950), caused by mutation in the SYCE1 gene (611486) on chromosome 10q26; SPGF16 (617187), caused by mutation in the SUN5 gene (613942) on chromosome 20q11; SPGF17 (617214), caused by mutation in the PLCZ1 gene (608075) on chromosome 12p12; SPGF18 (617576), caused by mutation in the DNAH1 gene (603332) on chromosome 3p21; SPGF19 (617592), caused by mutation in the CFAP43 gene (617558) on chromosome 10q25; SPGF20 (617593), caused by mutation in the CFAP44 gene (617559) on chromosome 3q13; SPGF21 (617644), caused by mutation in the BRDT gene (602144) on chromosome 1p22; SPGF22 (617706), caused by mutation in the MEIOB gene (617670) on chromosome 16p13; SPGF23 (617707), caused by mutation in the TEX14 gene (605792) on chromosome 17q22; SPGF24 (617959), caused by mutation in the CFAP69 gene (617949) on chromosome 7q21; SPGF25 (617960), caused by mutation in the TEX15 gene (605795) on chromosome 8p12; SPGF26 (617961), caused by mutation in the TSGA10 gene (607166) on chromosome 2q11; SPGF27 (617965), caused by mutation in the AK7 gene (615364) on chromosome 14q32; SPGF28 (618086), caused by mutation in the FANCM gene (609644) on chromosome 14q21; SPGF29 (618091), caused by mutation in the SPINK2 gene (605753) on chromosome 4q12; SPGF30 (618110), caused by mutation in the TDRD9 gene (617963) on chromosome 14q32; SPGF31 (618112), caused by mutation in the PMFBP1 gene (618085) on chromosome 16q22; SPGF32 (618115), caused by mutation in the SOHLH1 gene (610224) on chromosome 9q34; SPGF33 (618152), caused by mutation in the WDR66 gene (618146) on chromosome 12q24; SPGF34 (618153), caused by mutation in the FSIP2 gene (615796) on chromosome 2q32; SPGF35, caused by mutation in the QRICH2 gene (618304) on chromosome 17q25; SPGF36 (618420), caused by mutation in the PPP2R3C gene (615902) on chromosome 14q13; SPGF37 (618429), caused by mutation in the TTC21A gene (611430) on chromosome 3p22; and SPGF38 (618433), caused by mutation in the ARMC2 gene (618424) on chromosome 6q21.

X-linked forms of spermatogenic failure include SPGFX1 (305700) and SPGFX2 (309120).

Y-linked forms of spermatogenic failure include SPGFY1 (400042) and SPGFY2 (415000).

Spermatogenic failure can also result from underlying endocrinologic disorders (see, e.g., hypogonadotropic hypogonadism, 146110) or ciliary dyskinesias (see, e.g., CILD1, 244400).

Clinical Features

Ferguson-Smith (1973) noted that 8 cases of infertility were known in which a deficiency in synapsis during meiosis is evident by a deficiency of chiasmas in meiotic preparations from the testes. Since 3 of the males had first-cousin parents, the disorder is very likely to be autosomal recessive. Defective DNA repair was reported in the patient of Pearson et al. (1970), but Page (1973) could not demonstrate a defect in the patients she studied. The occurrence of a childless sister is also consistent with autosomal recessive inheritance (Baker et al., 1976; Hulten et al., 1974). Chaganti et al. (1980) described an inbred kindred with 2 affected sibs and reviewed the literature comprehensively.

Pathogenesis

Formation of a mature male gamete, the spermatozoon, involves an interplay of endocrine factors within the hypothalamic-pituitary-gonadal axis and of autocrine, paracrine, and juxtacrine interactions between the spermatogenic germ cells within the seminiferous tubules and the somatic cells that reside inside (Sertoli cells), between (Leydig and other interstitial cells), and within the walls (myoid cells) of the tubules, as well as of factors in the epididymis, a major maturation site for sperm. The process of spermatogenesis involves the renewal and differentiation of spermatogonial stem cells into rapidly proliferating spermatogonia, meiotic cells (spermatocytes), and haploid cells (round, elongating and elongated spermatids) before release of a spermatozoon into the tubule lumen. An amazingly large number of genes (approximately 1 in 25 of all mammalian genes) are specifically expressed in the male germline, exemplifying the complexity of the spermatogenic process and indicating that mutations in thousands of different genes could cause male infertility. It is likely that this complexity contributes to the large number of unresolved idiopathic infertility cases in male humans (summary by Matzuk and Lamb, 2008).

In Drosophila, the Boule gene (see 606165) encodes a key factor of meiosis in male germ cells, regulating the expression of 'twine,' a cdc25 phosphatase, which promotes progression through meiosis. Luetjens et al. (2004) investigated whether a common mechanism underlies the block of germ cell maturation observed in idiopathic and nonidiopathic azoospermic patients with meiotic arrest. They examined, by immunohistochemistry, expression of BOULE and CDC25A phosphatase (116947), the human homolog of twine, in 47 men with meiotic arrest, mixed atrophy, or normal spermatogenesis. The presence of genetic alterations in the BOULE gene was investigated by SSCP. BOULE protein expression in men with complete spermatogenesis was restricted to stages from leptotene up to stages of late spermatocytes, whereas CDC25A expression ranged from leptotene spermatocytes to elongating spermatids. Although spermatocytes were present in all testicular biopsies with meiotic arrest (28 testes), BOULE protein expression was completely lacking. In addition, in nearly all biopsies in which BOULE was absent, CDC25A was concomitantly lacking. However, no mutations or polymorphisms in the BOULE gene were identified that could explain the lack of BOULE or CDC25A expression. The authors concluded that a major group of infertile men with meiotic arrest lack BOULE protein and its putative target, CDC25A expression. They also concluded that spermatogenic failure seems to arise from factor(s) upstream of BOULE, which are possibly involved in regulating transcription and/or translation of BOULE.

Molecular Genetics

Associations Pending Confirmation

Azoospermia may be associated with variation in the HSF2 gene (see 140581.0001) or in the PLK4 gene (see 605031.0004).

For discussion of a possible association between variation in the DMRT1 gene (602424) and spermatogenic failure, see 602424.0001.

Some forms of male infertility may be associated with variation in the protamine genes PRM1 (see 182880) and PRM2 (see 182890).

Male infertility may be associated with variation in the NPAS2 gene (see 603347).

Male infertility may be associated with variation in the CFAP65 gene (see 614270).

Male infertility due to azoospermia may be associated with variation in the DNAH6 gene (see 603336).

Male infertility due to azoospermia may be associated with variation in the STX2 gene (see 132350).

For discussion of a possible association between spermatogenic failure and variation in the DMC1 gene, see 602721.0001.