About 20–30% of infertility is caused by male factors [
31]. The sex chromosomes (X and Y) in men play key roles in germ cell development. Both chromosomes contain a single copy of genes that are uniquely expressed in male spermatogenesis [
20]. In the last decade, extensive efforts have been made to clarify the exact nature of male infertility; however, a large number of infertile men are diagnosed as having “idiopathic infertility”. It has been demonstrated that the common genetic causes for male azoospermia are Y chromosome deletion and chromosomal abnormalities such as Klinefelter syndrome (47, XXY karyotype), and these genetic causes are responsible for ~ 25% of spermatogenic failure in males [
32,
33]. In the past decade, new technologies including array comparative genomic hybridization (ACGH), single nucleotide polymorphism (SNP) arrays, and next-generation sequencing have been used to detect infertility-related genetic defects [
17,
20,
30]. A systematic genomic screening of mouse spermatogonia has demonstrated that the genes expressed specifically in male germ cells and located in the X chromosome play a critical role in early spermatogenesis [
15].
Since
TEX11 is essential for meiotic recombination and chromosomal synapsis and
TEX11 deficiency causes meiotic arrest and male infertility, the identification of
TEX11 mutations has become attractive to determine the underlying causes of male infertility, especially in men with azoospermia. It has been found that
TEX11 mutations are diverse and present in various forms, such as missense and silent mutations, intronic alterations, frameshift mutations, and hemizygous deletions. Currently, 46 different
TEX11 mutations have been identified, including 24 in azoospermic men and 22 in fertile subjects [
4,
21]. The incidence of the
TEX11 mutation in azoospermic men from Germany with a European descent was only 2.4% (7/289), while its prevalence was 14.5% (35/246) in American azoospermic males [
4,
21]. It would be interesting to know whether this discrepancy is caused by the ethnicity. Two recent studies extensively investigated
TEX11 mutations in a large cohort of infertile/azoospermic men [
4,
21]. Yatsenko et al. have identified six different
TEX11 mutations, including loss of exons 9–11 (607del237bp), three splicing mutations (405C → T, 748 + 1G → A, and 1793 + 1G → C), and two missense mutations (466A → G and 2047G → A) (Table
2) [
21]. In addition, Yang et al. have carried out a more comprehensive sequencing analysis of
TEX11 exons and flanking introns in a large number of patients with nonobstructive azoospermia and fertile controls. They identified a total of 40 different sequence variants of
TEX11 in all subjects, but 22 different
TEX11 mutations (including three singletons) were observed in fertile controls, suggesting that these mutations are not linked to spermatogenic failure [
4]. Eighteen of the 21 singletons were found in patients with azoospermia, which included five exonic missense mutations (W117R, V142I, Q172R, T244I, and V748A), two exonic silent mutations (405C → T and 2319 T → C), one exonic frameshift mutation, and 10 intronic mutations (Table
2). Some subjects exhibit multiple
TEX11 mutations. Interestingly, many intronic alterations such as −48G → A and + 42C → A and silent mutations like 405C → T and 2319 T → C cause meiotic arrest, while some exonic missense mutations (K115R, M152 V, E436K, and D832E) have been found in fertile men [
4]. In the present study, we identified one novel exonic missense
TEX11 mutation (W856C) in two brothers but not their mother. Based on the testicular histology of two brothers, we observed a thicker basement membrane of the seminiferous tubules and poorly developed spermatocytes. No post-meiotic round spermatids or mature spermatozoa were observed in the seminiferous tubules, suggesting that this mutation will cause meiotic arrest. Moreover, Yatsenko et al. have observed that TEX11 expression is absent in the majority of seminiferous tubules but can be seen in rare tubules with remaining late spermatocytes and round spermatids [
21]. In contrast, we found positive TEX11 staining in all seminiferous tubules, with strong expression in spermatogonia and weak expression in spermatocytes. This difference is probably due to different
TEX11 mutation sites or antibody specificity. Although the precise causes for most
TEX11 mutations remain unclear, Yang et al. have verified that one frameshift mutation of
TEX11 in an azoospermic man with meiotic arrest was inherited from his mother because his mother was heterozygous for this mutation and his brother was azoospermic [
4]. Interestingly, we observed the same
TEX11 mutation in two brothers from a family without a history of infertility, whereas their mother had the wild-type allele of
TEX11. The abundance of
TEX11 mutations increases the difficulty in identifying which mutations will cause male infertility.
Table 2
Mutations of TEX11 detected in patients with azoospermia*
Exon 6 | 405C→T | Silent mutation, A135spl d # | Few sperm | 1 | 21 |
Exon 7 | 466A→G | Missense mutation, M156V | No sperm | 1 |
Exons 9–11 | 607del237bp | 203del79aa | Few sperm | 2 |
Intron 10 | 748+1G→A † | L249spl d # | No sperm | 1 |
Intron 21 | 1793+1G→C † | R597spl d # | No sperm | 1 |
Exon 24 | 2047G→A | Missense mutation, A683T | Few sperm | 1 |
Exon 6 | 349T→A | Missense mutation, W117R | No sperm | 1 | 5 |
Exon 6 | 405C→T | Silent mutation | No sperm | 1 |
Exon 7 | 424G→A | Missense mutation, V142I | No sperm | 1 |
Exon 7 | 515A→G | Missense mutation, Q172R | No sperm | 1 |
Exon 10 | 731C→T | Missense mutation, T244I | No sperm | 1 |
Exon 16 | 1258Ins (TT) | Frameshift mutation; 1258GATG→TTGGTA | No sperm | 1 |
Exon 26 | 2243T→C | Missense mutation, V748A | No sperm | 1 |
Exon 27 | 2319T→C | Silent mutation | No sperm | 1 |
Intron 3 | −17T→C † | Intronic alteration | No sperm | 1 |
Intron 5 | −48G→A † | Intronic alteration | No sperm | 1 |
Intron 10 | +42C→A † | Intronic alteration | No sperm | 1 |
Intron 12 | −28T→C † | Intronic alteration | No sperm | 1 |
Intron 15 | −64G→A † | Intronic alteration | No sperm | 1 |
Intron 21 | −1G→A † | Alteration of splicing acceptor site | No sperm | 1 |
Intron 22 | −37A→G † | Intronic alteration | No sperm | 1 |
Intron 24 | +119G→A † | Intronic alteration | No sperm | 1 |
Intron 27 | −55A→C † | Intronic alteration | No sperm | 1 |
Intron 28 | −44A→G † | Intronic alteration | No sperm | 1 |
Exon 29 | 2568G→T | Missense mutation, W856C | No sperm | 2 | This study |