Human Reproduction, Vol. 16, No. 7, 1365-1371,
July 2001
© 2001 European Society of Human Reproduction and Embryology
Genetic sperm defects and consanguinity
1 Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Applied Biology, University of Siena, 2 C.N.R. Center for the Study of Germinal Cells, and 3 Regional Referential Center for Male Infertility, Azienda Ospedaliera Senese, Via T. Pendola, 62, 53100 Siena, Italy
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Abstract |
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BACKGROUND: The existence of a genetic component to human infertility has been suggested, although neither the specific abnormalities involved, nor their genetic mechanism of transmission, are currently defined. We have examined, by transmission electron microscopy (TEM), ejaculate from 1600 males with fertility problems. Among the subjects studied, we focused on a group of patients whose family histories revealed different degrees of consanguinity, in order to evaluate the relationship between consanguinity and particular sperm alterations. METHODS AND RESULTS: A total of 64 consanguineous individuals were identified. In this group, excluding two azoospermic patients, 17 patients (27%) were found to have well recognized genetic ultrastructural defects affecting their entire sperm population: eight subjects had spermatozoa with `stunted tails', four `detached tail' spermatozoa, two `Kartagener's syndrome', two `miniacrosome' and one `round headed' spermatozoa. Since these alterations affect the total sperm population and do not respond to medical treatment, they are suspected of having a genetic origin. The remaining group of 1506 non-consanguineous patients suffered from the same genetic defects in only 15 cases (<1%). CONCLUSIONS: From the data presented, it appears that some very peculiar and rare sperm defects may have a genetic basis since they occur more frequently in consanguineous patients, and are related to different degrees of consanguinity. Since the ejaculate of the remaining patients, both consanguineous and not, showed diverse types of ultrastructural sperm anomalies that did not affect the entire sperm population, they might represent pathologies lacking a genetic basis.
Key words: consanguinity/genetic defects/male infertility/spermatozoa/ultrastructure
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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In 1994 Lilford et al. proposed that human male subfertility, related to oligoasthenoteratospermia, has a familial component (Lilford et al., 1994
). However, they neither characterized the kinds of sperm abnormalities involved, nor produced a demonstration of the genetic mechanism of transmission. In recent years, it has become more and more evident that male infertility is correlated with sperm structure, which is completely different from that of healthy individuals (Figure 1). In fact, the submicroscopic evaluation of sperm characteristics allows the grouping of infertile patients into categories of pathologies (Figure 2) such as immaturity, necrosis, apoptosis and autoantibodies (Baccetti et al., 1995). Most of the causes of these pathologies (infections, varicocoele, hormonal alterations, etc.) are well known and can be successfully treated by drugs or by surgery. Moreover, it has been observed that in a few cases, all the spermatozoa of a sterile individual are affected by only one identical, precise, monomorphic specific alteration. The spermatozoa of these patients will always be infertile because alterations of this kind are not curable, and are present in the whole ejaculate for life, without fluctuations. Occasionally these defects have been detected in sterile brothers or in sterile patients with consanguineous ancestry (first, second or third cousins). Therefore the affections have sometimes been suspected of having a genetic origin.
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The most frequent sperm defects of supposed genetic origin, quoted in the literature, are here reported:
- (i)The `crater defect' (Figure 3).
- (ii)The `round headed' (Figure 4
) defect. Assisted reproduction by intracytoplasmic sperm injection (ICSI) had positive results (Lundin et al., 1994; Bourne et al., 1995, Kilani et al., 1998).
- (iii)The `miniacrosome sperm defect' (Figure 5
). This defect is also known as `acrosomal hypoplasia' (Zamboni, 1987). This malformation was found in two siblings (Baccetti et al., 1991). One patient with this defect obtained fertilization only by ICSI (unpublished data).
- (iv)The `stunted tails' (Figure 6
) including the `stump defect' and the `short tail.' Several authors (Stalf et al., 1995; Favero et al., 1999) obtained a successful ICSI by stunted tail spermatozoa. Others (Bisson et al., 1979; Chemes et al., 1998) suggested a genetic origin of the defect. A similar defect concerns ejaculates showing various dimensions of the tail, which is, in all cases, affected by fibrous sheath dysplasia (which is an affection typical of `stunted' tails, discovered by Ross et al. 1971 and mentioned by Holstein and Schirren, 1979). Brugo Olmedo et al. obtained positive ICSI with human spermatozoa affected by this defect (Brugo Olmedo et al., 1997). Moreover Baccetti et al. found this defect in two unrelated men affected by a pericentric inversion in chromosome 9 (Baccetti et al., 1997). Quite recently, Anderson and Makinen found the stunted tail defect in boars and transmitted the defect by ICSI to the next generation (Anderson and Makinen, 2000). The genetic origin of the defect is suspected.
- (v)The `Kartagener syndrome' (immotile cilia, immotile sperm tail and 50% `situs inversus') (Figure 7
). Eliasson et al. (1977) and Afzelius and Eliasson (1979) proposed a multigenic inheritance for the phenotypic variations of this syndrome (Eliasson et al., 1977; Afzelius and Eliasson, 1979); others (Rott, 1983; Edwards et al., 1989; Walter et al., 1990) proposed one gene defect with autosomal segregation pattern. The ICSI was successful (Nijs et al. 1996).
- (vi)The `detached tail' spermatozoa (Figures 8, 9
). Observed also in two siblings (Baccetti et al., 1989). Also, Chemes et al. found this defect in 10 young sterile patients including two brothers and suggested that this is a genetic defect (Chemes et al., 1999).
- (vii)The `9+0 axoneme ` and the `absent axoneme.'
- (ii)The `round headed' (Figure 4
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Among these seven categories of defects, the first three concern the sperm head, while the tail is normally motile, the last three concern the tail, while the head is normal. In both groups ICSI has been successfully attempted: namely in `round headed,' `miniacrosome,' `stunted tail' and `dynein arms deficiency.'
In the years 1990–2000, we examined, by transmission electron microscopy (TEM), the ejaculate of a large population of sterile patients. The ultrastructural observations of spermatozoa have been evaluated by the mathematical-statistical formula of Baccetti et al. (Baccetti et al., 1995). The family history of the patients has been considered. Many epidemiological and statistical studies of consanguineous marriages have been carried out in the past, particularly because this kind of marriage is traditional and very common in Middle Eastern culture. Inbreeding is known to have adverse effects on morbidity and mortality, particularly in relation to autosomal recessive disorders, which are more than twice as common in inbreeding (Hoodfar and Teebi, 1996). Inbreeding increases the power to detect the role of a recessive or a quasi-recessive disease susceptibility factor (Genin and Clerget-Darpouxn, 1996). Effects of inbreeding on the fertility and primary sterility of couples were investigated in marriages among uncles and nieces or among first or second degree cousins. On the contrary, the level of primary sterility was found to be similar both in consanguineous and in non-consanguineous couples (Edmond and De Braekeleer, 1993).
In this paper, we present the results of the study performed on our large group of infertile patients, some of them characterized by consanguinity of various degrees. The sperm submicroscopical characteristics were analysed by TEM, in order to evaluate the relationship between consanguinity and sperm alterations.
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Materials and methods |
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Patients
From January 1990 to October 2000, our laboratory examined 1600 male patients. Usually the patients attended for semen analysis after several years of couple sterility. The patients were interviewed about their case histories and their reproductive problems, their family background, and their possible consanguinity. The interview was followed by a physical examination in order to identify anatomical problems. Routine checking of the level of testosterone, cortisol, oestradiol, FSH, LH, prolactin, TSH, T3 and T4 in blood was performed. The semen and urethral fluid were tested for microbial infections.
We identified a group of male patients presenting different degrees of consanguinity in their history. Among them were siblings (1/2 consanguinity), sons of 1st degree cousins (therefore their chance of homozygosity was 1/16), sons of 2nd degree cousins (their chance of homozygosity was 1/64) and sons of 3rd degree cousins (their chance of homozygosity was 1/256).
Light and transmission electron microscopy
Ejaculates obtained by masturbation after at least 3 days of sexual abstinence were examined after liquefaction: for each sample, pH, sperm concentration and progressive motility at 30 min were evaluated. For electron microscopy, spermatozoa were fixed in cold Karnovsky fixative and maintained at 4°C for 2 h. The fixed semen was centrifuged at 3000 g for 15 min. The fixed pellet was removed from the centrifuge tubes, washed in 0.1 mol/l cacodylate buffer (pH 7.2) for 12 h, postfixed for 1 h at 4°C in 1% buffered osmium tetraoxide, dehydrated and embedded in Epon Araldite. Ultrathin sections were cut with an ultramicrotome (Supernova; Reickert Jung, Vienna, Austria) and collected on copper grids, stained with uranyl acetate and lead citrate, observed and photographed with a Philips CM 10 electron microscope (Philips Scientifics, Eindhoven, The Netherlands). Submicroscopical characteristics of sperm organelles were evaluated using the mathematical statistical formula of Baccetti et al. which calculates the number of spermatozoa free of structural defects (`healthy') (Baccetti et al., 1995). On the basis of this ultrastructural evaluation, the presence or absence of genotypic sperm defects was identified.
Statistical analysis
The frequencies of the values of the supposed genetic sperm defects were calculated and compared between the consanguineous patients and the non-consanguineous patient groups, using the 
2-test.
In order to test the possibility that consanguinity may influence only the phenotypic characteristics, a randomized trial was designed. Non-consanguineous patients, ranging from 16 to 46 years, were grouped into seven classes of age, excluding the carriers of genotypic sperm defects. Subsequently, the consanguineous patients, excluding the carriers of genotypic sperm defects, were grouped in the same seven classes of age. The class widths were equal. According to the number of consanguineous individuals (cases) distributed in each age class, the same number of non-consanguineous ones (controls) was randomly assigned in the same correspondent class.
The Shapiro–Wilk W-test was used to determine whether values conformed to a normal distribution. Where the data were normally distributed, the Student t-test between independent groups was performed, where they were not, the Mann–Whitney U-test was used to compare the values of the percentage motility, the `healthy' sperm numbers and percentages in the carriers of only non-genetic sperm defects (phenotypic) between the two groups (cases and controls). Statistical significance was set as P < 0.05.
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Results |
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The seminological characteristics of 1600 sterile male individuals was analysed by light and electron microscopy over a 10-year period; 32 (two consanguineous and 30 non-consanguineous) were azoospermic and were ruled out from this research. The number of the infertile patients studied was therefore reduced to 1568; 62 were involved in situations of consanguinity of various degrees.
Various degrees of consanguinity
The 1/2 degree consanguinity (sib-ship) group included a pair of sterile siblings, carriers of `miniacrosome' (acrosome hypoplasia) (Table I), a defect clearly affecting the total sperm population and candidate for a genetic nature. A further very interesting case is a triplet of sterile siblings, affected by the genetic defect `stunted' tail (`stump`) in the total sperm population (Table I). A third, more peculiar case, is that of a pair of siblings (1/2 consanguinity) with consanguineous parents (1/64 degree cousins). They represented a sib-ship with the characteristic of `detached tail' spermatozoa (Table I). In our case record, we have also observed three pairs of siblings devoid of any genotypic sperm defect. In total (Table II), the 13 observed 1/2 consanguineous males presented seven carriers of a genotypic sperm defect (55%).
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Patients having a chance of homozygosity of 1/16, 1/64 or 1/256 are descendants of ancestors sharing respectively 1/8, 1/32 and 1/128 of genes. This group comprised 49 patients (Table II
). Transmission electron microscopy analysis revealed a high incidence of sperm defects of supposed genetic origin. In fact, in 10 out of the 49 individuals (20%), their total sperm populations were affected by one of these genotypic defects. In this group, five patients with the `stunted tails`, two patients with the `immotile cilia syndrome and situs inversus (Kartagener syndrome)', two patients with `detached tail' spermatozoa, and one patient with `round headed' spermatozoa were observed. The other 39 patients were not affected by genotypic defects. A few showed some evidence of this kind of genotypic affections in their relatives.
In total, the 62 consanguineous individuals included 17 cases of genotypic sperm defects (27.5%) (Figure 10). It is interesting to distribute the percentages of genotypic sperm defects in the four major classes of consanguinity explored in this study (Table II). In siblings (1/2 of consanguinity), seven out of 13 patients were affected (54%), while the smaller degrees of consanguinity, due to consanguineous ancestors, gradually reduce the percentage of patients affected, passing from 30%, to 15%, to 0% (Figure 11).
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Group of 1506 sterile individuals free from consanguinity conditions
In this large group of infertile men, only 15 showed the total sperm population affected by the classic defects of supposed genetic origin. The percentage of genetic defects, in the group of 1506, was therefore <1% (Figure 10
). The observed defects were `round headed' (six cases), `stunted tails' (five cases), `Kartagener syndrome' (two cases), `axoneme less' (one case) and `miniacrosome' (one case). As is evident, the difference between the percentages of genetic sperm defects (1% in non-consanguineous category, 27.42% in the consanguineous category) is very high (Figure 10). The link between genetic defects and consanguinity is significantly proved by the results of the 2-test calculated among the frequencies of consanguineous and non-consanguineous patients with regard to genetic defects (P > 0.01 in both situations).
Sperm ultrastructure and motility percentage in 1536 sterile men, free from genotypic defects: consanguineous versus non-consanguineous
Ultrastructural sperm examination of 45 of the 62 consanguineous patients confirmed the absence of genotypic defects and assessed in each patient only the presence of well-known defects of a phenotypic nature concerning the various sperm organelles, without affecting the whole sperm population. It is interesting to observe that among these 45 patients, one, a Mediterranean anaemia carrier, had two sisters affected by `Kartagener syndrome'. In the same group, three patients had sterile brothers and a fertile brother of one of these patients had two daughters affected by neuro-psychomotor disorders. Therefore it can be assumed that even if genetic sperm defects are not evident, the genome of some consanguineous sterile men contains some recessive factor which may become evident in homozygosity. In this case, the percentage of consanguineous carriers of genotypic sperm defects could be still larger. Also in this event, more than half of the consanguineous individuals would be affected by only phenotypic sperm defects, as are most of the non-consanguineous patients.
In order to substantiate the assumption that the two groups contain spermatozoa with only phenotypic defects, the ultrastructural and kinetic sperm characteristics of the 45 randomly allocated consanguineous individuals (cases) were compared with 45 non-consanguineous patients (controls) also not affected by genotypic defects. The mean percentage progressive motility for the spermatozoa in the consanguineous patient group was 20.35%, whereas in the other group it was 27.18%. When the percentage motility values of these two groups were compared, a significant difference was found using the Mann–Whitney U-test (P = 0.02), as well as the t-test (P = 0.03). However, as regards ultrastructure, the percentages of `healthy' spermatozoa, and the total numbers of `healthy' spermatozoa in the two groups (cases and controls), calculated by the formula of Baccetti et al. (Baccetti et al., 1995), did not differ (Mann–Whitney U-test).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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On the basis of a large case record on male infertility (1600 individuals), azoospermic patients were excluded and 62 patients were found to have some degree of consanguinity. In this group, 17 (25%) carriers of well-recognized genetic ultrastructural sperm defects were noted: eight carriers of `stunted tail', four of `decapitated' spermatozoa, two of `Kartagener syndrome', two of `miniacrosome' and one of `round headed' spermatozoa. Moreover, in the 45 individuals with consanguineous relationships, but apparently devoid of the classic genetic sperm defects, three cases were found to have relatives affected by sterility, `Kartagener syndrome' or neuromotor problems. This could indicate a still larger number of genetic defects in the consanguineous category.
In conclusion, the presence of genetic sperm defects is clearly related to consanguinity. Most of these defects, inducing male sterility, seem to be due to recessive autosomal mutations. This possibility has been envisaged both in `dynein arms deficiency syndrome' (Rott et al., 1983; Edwards et al., 1989; Walter et al., 1990) and in `stunted tail syndrome' (Bisson et al., 1979; Chemes et al., 1998), in `round headed,' in `miniacrosome' and in `detached tails'. These alterations affect particularly the tail organelles, namely fibrous sheath, axonemal tubules and accessory fibres, all of them favoured targets of mutations. As a consequence, sperm motility in most of the genetic sperm defects is completely absent or abnormal. A further interesting observation is that the portion of genes shared and the chance of homozygosity by descent are significantly related to the amount of genotypic sperm defects.
The remaining group of 1506 non-consanguineous individuals presented genotypic sperm defects in only 15 cases. The cause of these genotypic sperm defects in individuals devoid of consanguineous relationships is intriguing. Evidently, the presence of a not-declared or distant relationship cannot be excluded in the carriers of these alterations. However, in addition, it could be assumed that a proportion, usually very small, of the lethal genetic defects leading to infertility in the natural population arises from novel mutations. Moreover, we cannot exclude, for at least two (`round head' and `fibrous sheath dysplasia') of these defects, both relatively frequent in the non-consanguineous category, the possibility of a recessive mutation carried by the X chromosome and transmitted by the mother.
All the 1536 sterile patients whose spermatozoa were devoid of genotypic defects and were therefore affected only by phenotypic defects showed the same structural sperm quality both in the consanguineous (45 individuals) and in the non-consanguineous (1491 individuals) groups. This observation substantiates the role of consanguinity in inducing the conditions of homozygosity necessary to reveal genetic structural sperm affections.
In contrast, the percentage sperm motility was significantly lower in the 45 consanguineous patients with spermatozoa affected only by phenotypic defects. This discordant characteristic, evident in consanguinity but apparently devoid of any ultrastructural basis, could be dependent on a genetic defect not (or not yet) revealed by electron microscopy.
A very important aspect of this matter is the chromosomal localization of the mutations involved in sperm sterility. Sometimes attempts have been made to relate these defects to cytogenetic disorders. However, convincing indications of a chromosome region involved in the presence or in the absence of a characteristic with a mutation-deletion system have not yet been produced. Only Moss et al. (1997) in the mouse, reported the localization in the X chromosome of the AKAP82 gene that encodes for a major fibrous sheath protein (Moss et al., 1997). At present, there are no reports of gene anomalies in human patients with fibrous sheath dysplasia (Chemes et al., 1998). Baccetti et al. (1997) reported many sperm tail alterations (including dysplasia in the fibrous sheath) in the total sperm population of two unrelated carriers of the same autosomal (chromosome 9) pericentric inversion (Baccetti et al., 1997). However, the large number of sperm characteristics involved suggests that this chromosome region could also have a general role in spermatogenesis. Ramesh and Verma (1996) observed that the same chromosome alterations have no phenotypic consequences in spermatozoa (Ramesh and Verma, 1996).
Therefore, the current data on consanguinity substantiate the demonstration that several very peculiar, monomorphic and rare sperm defects, affecting the total sperm population of sterile men, have a genetic basis. Most of them are probably determined by a recessive autosomal mutation.
A consequence of this demonstration is that these mutations present in spermatozoa can be transmitted to the offspring by the ICSI technique (Anderson and Makinen, 2000) overcoming the usual impossibility of oocyte penetration by the affected spermatozoa. At least in the case of patients with high degrees of consanguinity, an accurate sperm ultrastructural examination of the ejaculate is recommended before starting an ICSI procedure.
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The authors wish to thank the MURST Projects Ex 40% and 60% as well as the MURST-CNR Biotechnology Program L. 95/95.
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4 To whom correspondence should be addressed at: Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Applied Biology, Via T. Pendola, 62, 53100 Siena, Italy. E-mail: baccetti{at}unisi.it
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References |
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Submitted on December 29, 2000; accepted on March 22, 2001.
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B. Baccetti, E. Bruni, G. Collodel, L. Gambera, E. Moretti, R. Marzella, and P. Piomboni 10, 15 reciprocal translocation in an infertile man: ultrastructural and fluorescence in-situ hybridization sperm study: Case report Hum. Reprod., November 1, 2003; 18(11): 2302 - 2308. [Abstract] [Full Text] [PDF]
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 T. Davies and S. Varmuza Development to Blastocyst Is Impaired When Intracytoplasmic Sperm Injection Is Performed with Abnormal Sperm from Infertile Mice Harboring a Mutation in the Protein Phosphatase 1c{gamma} Gene Biol Reprod, April 1, 2003; 68(4): 1470 - 1476. [Abstract] [Full Text] [PDF]
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G. Porcu, G. Mercier, P. Boyer, V. Achard, J. Banet, M. Vasserot, C. Melone, J. Saias-Magnan, C. D'Ercole, C. Chau, et al. Pregnancies after ICSI using sperm with abnormal head-tail junction from two brothers: Case report Hum. Reprod., March 1, 2003; 18(3): 562 - 567. [Abstract] [Full Text] [PDF]
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