Recombination in men with Klinefelter syndrome

Abstract

Klinefelter syndrome (KS: 47,XXY), occurs in one in 1000 male births. Men with KS are infertile and have higher rates of aneuploidies in sperm compared with normal fertile men. In the course of analyzing recombination in a population of infertile men, we observed that four men in our study presented with KS. We examined whether these men differed in recombination parameters among themselves and relative to normal men. Even though the number of men with KS analyzed was small, we observed remarkable variation in spermatogenesis. In spite of the fact that the men had the same genetic cause for infertility, two of four KS patients had few or no spermatogenic cells that progressed through meiosis to the pachytene stage, whereas the other two men produced abundant pachytene cells that had recombination frequencies comparable with those of fertile men, although one had a significant reduction in fidelity of synapsis. Moreover, regardless of histological appearance, examination of outcomes of assisted reproduction indicated that sperm were extracted from testis biopsies in all four cases, and when used in assisted reproductive practices chromosomally normal babies were born. These results reinforce that: (i) men with the same underlying genetic cause for infertility do not present with uniform pathology, (ii) the checkpoint machinery that might arrest spermatogenesis in the face of chromosomal abnormalities does not prevent pockets of complete spermatogenesis in men with KS, and (iii) aneuploidy, in some cases, is compatible with birth of a chromosomally normal child, suggesting that sperm produced from a background of aneuploidy can be normal in men with KS.

Investigation of AZF microdeletions in patients with Klinefelter syndrome

“…KFS patients are often classified as having azoospermia, but there are reports stating that some KFS patients can produce normal sperm (Gonsalves et al, 2005). In contrast, some patients may have no sperm in the semen, but a few sperm exit in the testis (Lanfranco et al, 2004).…”

Ploidy of spermatogenic cells of men with non-mosaic Klinefelter’s syndrome as measured by a computerized cell scanning system

“…Two approaches on the ability of 47,XXY testes to yield postmeiotic cells exist. According to some researchers, 47,XXY spermatogonia have the potential to complete meiosis, resulting in both the increase in sex chromosomal aneuploidy rates as well as the presence of normal (haploid) spermatozoa [6,7,19,21,23]. According to others, primary 47,XXY spermatocytes are unlikely to complete meiosis, and spermatozoa of KS men arise from the patches of 46,XY spermatogonial stem cells in the testes that are affected by a compromised testicular environment and produce a high rate of aneuploid sperm due to meiotic errors.…”

“…They were reinforced by Egozcue et al [35] who identified the absence of 46,XY spermatogonia in patients negative for spermatids and spermatozoa, and by Mroz et al [36] who showed a clear absence of meiotic competence of 47,XXY cells in mice. Small quantities of studied germ cells such as 20-100 spermatogonia and primary spermatocytes in very few biopsies [1][2][3][4][5]8], as well as technical shortcomings, preclude a definite conclusion [1,4,17,19,20,23] (the study by Yamamoto et al [23] (2002) included 12 biopsies, but lacked information regarding the number of meiotic cells). The CCSS technique, which is based on corresponding size and morphology of the cells and their FISH images, enabled an extended study at three levels:…”

“…Researchers have used various ways to find out the cause for the presence or absence of these euploid and aneuploid spermatozoa and to investigate their origin and precursor cells. Since in vitro experiments are not yet available, some have looked at progenitor germ cells and the meiotic process itself in vivo, for example, using fluorescence in situ hybridization (FISH) on pachytene figures (the meiotic stage during which crossing-over occurs) [4,17,1,[19][20][21][22][23]. Others [5-7, 11, 24] have used an indirect approach and have deduced the most likely hypothesis from FISH results on spermatozoa, i.e., the Bend product^of the meiotic process.…”

Human Male Meiosis and Sperm Aneuploidies

“…Additionally, immunocytogenetics can be combined with FISH to analyze recombination rates and crossover placement in individual chromosomes. While this assay also requires testicular biopsies to obtain material, pachytene has a long duration and nuclei are not as condensed as in diakinesis (Gonsalves et al, 2004(Gonsalves et al, , 2005Judis et al, 2004;Lynn et al, 2002;Ma et al, 2006;Sun et al, 2004aSun et al, , 2004bSun et al, , 2006Sun et al, , 2007Sun et al, , 2008aSun et al, , 2008b.…”