Molecular Human Reproduction, Vol. 6, No. 1, 1-4,
January 2000
© 2000 European Society of Human Reproduction and Embryology
Genetic diagnosis |
No evidence for uniparental disomy of the sex chromosomes in idiopathic male infertility
1 Institute of Human Genetics of the University, Vesaliusweg 12–14, D-48149 Münster, Germany, and 2 Institute of Reproductive Medicine of the University, Domagkstr. 11, D-48129 Münster, Germany
Abstract
Uniparental disomy (UPD) is a rare genetic aberration characterized by the uni- rather than biparental inheritance of a pair of homologous chromosomes. Among the various adverse clinical effects that UPD can have in humans, abnormalities of the male reproductive system have been described in UPD of the chromosomes 7, 11, 14 and 15. Given the considerable rate of sex chromosomal aneuploidy in human gametes and zygotes, we postulated that paternal uniparental disomy of the sex chromosomes might be a cause of otherwise unexplained male infertility. With a set of highly polymorphic DNA markers the parental origin of the X chromosome in 41 men with severe idiopathic infertility was determined. In all patients the X chromosome was derived from the mother, indicating regular biparental inheritance of the sex chromosomes. We thus obtained no evidence that paternal uniparental disomy of the X and Y chromosomes is a mechanism underlying idiopathic male infertility.
male infertility/sex chromosomes/uniparental disomy
Introduction
The basic cause of male infertility remains obscure in ~30% of the cases (Nieschlag, 1997
). For lack of better understanding such patients are assigned diagnoses such as idiopathic male infertility or idiopathic oligozoospermia. The importance of genetic factors in the causation of seemingly idiopathic spermatogenic failure has become more and more obvious (Hargreave et al., 1998; Kleiman et al., 1999; Oates, 1999). Various numerical and structural chromosomal anomalies can result in oligo- or azoospermia (Van Assche et al., 1996). Also, several single gene defects cause male reproductive failure (Meschede and Horst, 1997). However, a major part of oligo- and azoospermia cases still remain aetiologically unaccounted for, leaving room for speculation about yet-undetected genetic and environmental factors affecting male fertility.
The importance of uniparental disomy (UPD) as a pathogenetic mechanism of various human diseases was only recently recognized (Engel, 1993). UPD entails the non-Mendelian inheritance of a pair of homologous chromosomes (or parts of them) from one instead of both parents (Figure 1). This can result in adverse clinical consequences if chromosomes carrying parentally `imprinted' genes are involved. Such genes are expressed exclusively from either the maternal or the paternal allele. Uniparental disomy would thus result in over- or under-expression of one or more genes located in the imprinted domain. In addition, UPD can result in clinical disease through mechanisms other than those related to imprinting, e.g. by unmasking recessive mutations.
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Uniparental disomy of the human chromosomes 7, 11, 14 and 15 can adversely affect the male reproductive system (Meschede and Horst, 1997
). Thus far, nothing is known about the effect that sex chromosome uniparental disomy would have on human male fertility. Spermatogenesis is highly vulnerable to unbalanced and balanced sex chromosome aberrations, which often do not have extragonadal clinical manifestations (Gardner and Sutherland, 1996). We therefore postulated that, possibly through interference with X-chromosome imprinting (Cattanach and Beechey, 1990), uniparental inheritance of the sex chromosomes might selectively affect spermatogenesis in otherwise healthy men. Materials and methods
A total of 41 men with idiopathic severe oligozoospermia (<2x106 spermatozoa/ml in a single semen sample or <5x106 spermatozoa/ml in at least two consecutive samples) or non-obstructive azoospermia were recruited for the study. The cohort included two pairs of brothers (patients 7 and 11, and patients 39 and 40; see Table I). A karyotype was available for 25 of the 41 probands, and all had normal results. Findings of uncertain aetiological significance such as a small varicocele or a history of treated cryptorchidism were not an exclusion criterion. Blood for DNA extraction was collected from the probands and both their parents. All subjects involved in the study gave written informed consent. The study protocol was approved by the University Hospital's ethics committee.
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The parental origin of the probands' X chromosomes was determined through genotyping a set of highly polymorphic X-linked microsatellite markers in the delta aminolevulinate synthase-2 gene at Xp11.21 (ALAS2; Cox et al., 1992), in the androgen receptor gene at Xq11-q12 (AR1; Tilley et al., 1989), or in the dystrophin gene at Xp21.2 (DMD 5N3, IVS44-SK21, STR44, STR45; Clemens et al., 1991; King et al., 1994; Köchling et al., 1995). The analysis was limited to the X chromosome as the Y chromosome is always paternally derived. The number of markers tested per proband was at least two. More markers were analysed when the first two were not informative. Allele sizes of the microsatellite markers were determined with a semiautomatic sequencer. They were measured against an internal standard and do not represent absolute allele sizes.
Results
Informative results were obtained for all 41 patients. Without exception, their X chromosomes were of maternal origin, indicating regular biparental inheritance of the sex chromosomes. Table I
shows the results in detail.
Discussion
Uniparental disomy has been identified as a mechanism underlying various human disorders such as the Prader–Willi, Angelman, Russell–Silver, and Beckwith–Wiedemann syndromes (Ledbetter and Engel, 1995; Morison and Reeve, 1998; Kotzot, 1999). Among other possible clinical consequences, UPD of the chromosomes 7, 11, 14, and 15 can have adverse effects on the male reproductive tract (Meschede and Horst, 1997).
The ~0.1% rate of XY disomy in human spermatozoa (Williams et al., 1993; Griffin et al., 1995; Abruzzo et al., 1996) suggests that pregnancies where the male gamete has provided both an X and a Y chromosome could be relatively common. Through a mechanism termed aneuploidy correction (Engel, 1993) a zygote with originally three sex chromosomes could spontaneously revert to a normal set of XY sex chromosomes. Most X and Y chromosomal anomalies have dramatic adverse effects on male fertility (Hsu, 1994; Gardner and Sutherland, 1996). Moreover, in male mammals, including human, X chromosome inactivation is observed exclusively in the germ cell compartment of the testis, but not in somatic tissues (Salido et al., 1992). Given the obvious functional importance of the X chromosome for male germ cell development we postulated that UPD of the sex chromosomes might selectively compromise spermatogenesis and could thus represent a yet unrecognized cause of `idiopathic' male infertility. The data from the present study do not corroborate this hypothesis. Given the limited number of patients that were analysed, UPD of the sex chromosomes may still be a rare cause of male infertility.
We are aware of a single reported case with paternal UPD of the sex chromosomes. The proband was ascertained through a father-to-son transmission of haemophilia A (Vidaud et al., 1989). Unfortunately, the case report does not refer to the gonadal status of the proband. Recently, a man with 47,XXY Klinefelter syndrome, androgen insensitivity, and maternal uniparental disomy of his X chromosomes was reported (Uehara et al., 1999). Due to the concurrance of multiple genetic anomalies in this individual the case does not allow us to delineate the influence of sex chromosome UPD on male gonadal function. Mice with paternally-derived X and Y chromosomes are apparently fertile (Handel and Hunt, 1991). As imprinting effects are often species specific (Morison and Reeve, 1998), this animal model does not exclude an adverse effect of gonosomal UPD on human male fertility. Definitive evidence for or against a role of sex chromosome uniparental disomy in male reproductive failure could only come from the clinical characterization of a post-pubertal male known to have inherited both his sex chromosomes from his father.
In females, maternal and paternal UPD of the X chromosome was repeatedly observed (Avivi et al., 1992; Schinzel et al., 1993; Quan et al., 1997). Unfortunately, no information as to the fertility status of the probands is available. It thus remains to be determined which effects, if any, uniparental disomy of the sex chromosomes has on human gonadal function.
Notes
3 To whom correspondence should be addressed 
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Submitted on July 21, 1999; accepted on October 12, 1999.
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