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University of Padova, Department of Medical and Surgical Sciences, Clinica Medica 3, Center for Male Gamete Cryopreservation (A.F., M.S., L.B., G.R., A.B., C.F.), 35128 Padova, Italy; and University of Rome La Sapienza, Institute of Medical Genetics and Institute CSS-Mendel (T.D., B.D.), 00161 Rome, Italy
Address all correspondence and requests for reprints to: Prof. Carlo Foresta, University of Padova, Department of Medical and Surgical Sciences, Clinica Medica 3, Center for Male Gamete Cryopreservation, Via Ospedale 105, 35128 Padova, Italy. E-mail: carlo.foresta{at}unipd.it.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Evidence supporting a genetic cause of cryptorchidism is numerous. In some cases of unilateral cryptorchidism, the contralateral, normally descended testis may be altered too (6), and testicular cancer may originate from the contralateral, not retained testis (7). Furthermore, familial cases have been described (8, 9), and more recently, animal models suggested candidate genes for cryptorchidism. In particular, a role for a novel testicular hormone, Insl3 (insulin-like factor 3, whose product is also called relaxin-like factor) has been provided (10, 11). Insl3 is a member of the relaxin-insulin family, and it is expressed in pre- and postnatal testis Leydig cells and at reduced levels in postnatal ovarian thecal cells (12, 13). Insl3-/- male mice exhibit bilateral cryptorchidism due to impaired development of the gubernaculum (10, 11). The receptor for Insl3 has been recently identified and named Lgr8 (leucine-rich repeat-containing G protein-coupled receptor 8) or Great (G protein-coupled receptor affecting testis descent) (14). The correspondence between Insl3 as ligand and Lgr8/Great as receptor was suggested by the phenotype similarity between the Great mutant mice and the Insl3 knockout mutants (10, 11, 15, 16). Moreover, relaxin, a hormone belonging to the same family of Insl3, activates Lgr8/Great signaling through a cAMP-dependent pathway (14), and interactions between Insl3 and Lgr8/Great were demonstrated by ligand-receptor cross-linking (14, 17). The expression of Lgr8/Great is restricted to the testis, brain, and skeletal muscles, with the highest level of expression in the gubernaculum (14, 15). The INSL3-LGR8/GREAT system is supposed to influence the growth and thickening of the gubernaculum, allowing the testis to be retained in the inguinal region.
Several polymorphisms in both INSL3 and LGR8/GREAT genes have been reported previously, whereas only a few mutations specifically associated with cryptorchidism have been found (9, 16, 18, 19, 20, 21, 22, 23, 24, 25). Actually, cryptorchidism is a heterogeneous disorder, and testicular function may be altered at different degrees, with seminal quality ranging from normozoospermia to complete azoospermia (6). Therefore, it is difficult to derive a clear phenotype associated with mutations of INSL3 or LGR8/GREAT from these previous studies. In the present work we report a more comprehensive analysis by systematically looking at mutations in both of these genes in the same well characterized group of cryptorchid men. We show that the clinical consequence of alterations of this system is failure of the testis to descend correctly in the scrotum, without apparently affecting the spermatogenic and endocrine components of the testis itself.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Eighty-seven consecutive subjects (age, 24–45 yr) with history of maldescended testes referred to our center for fertility evaluation were recruited. Thirty-six men had bilateral cryptorchidism, and 46 had unilateral cryptorchidism. Age at orchidopexy ranged from 1–27 yr. The remaining five subjects reported failure of the testes to normally descend in the scrotum at birth with spontaneous descent in first years of life, and they still were affected by bilateral retractile testes. All 87 subjects were Caucasian from different regions of Italy. A careful history and physical examination were performed in all patients. At least two semen analyses were performed, following WHO recommendations (26), and in all subjects ultrasound examination of the testes was performed (for testis morphology and volume), and plasma FSH, LH, and testosterone concentrations were determined. When semen analysis repeatedly revealed azoospermia (absence of sperm) or oligozoospermia with sperm concentrations less than 10 million/ml, a bilateral testicular fine needle aspiration cytology (FNAC) (27) was performed. A total of 80 Italian men with absence of a clinical history of maldescended testes were used as controls.
Informed consent was obtained from each subject, and the authors’ institutional ethical committee approved the study.
Mutation analysis of INSL3 and LGR8/GREAT
Genomic DNA was extracted from peripheral blood of each patient and control. We used the LGR8/GREAT cDNA to blast search the chromosome 13 human sequence at the University of California at Santa Cruz Genome Bioinformatics (http://genome.ucsc.edu). We designed 17 pairs of intronic primers to amplify the 18 LGR8/GREAT exons (Table 1
). Genomic DNA was subjected to PCR, with the following conditions: denaturation at 94 C for 1 min, followed by 20 cycles of 94 C for 30 sec, 55 C (decreasing 0.5 C in each cycle) for 30 sec, and 72 C for 30 sec and 15 cycles of 94 C for 1 min, 45 C for 1 min, and 72 C for 1 min. The PCR products were submitted to single strand conformational polymorphism and/or were purified using shrimp alkaline phosphatase and exonuclease and direct sequenced using the same primers as for PCR. The single strand polymorphism analysis was performed in precast gel (ExcelGel, Amersham Pharmacia Biotech, Indianapolis, IN) following the manufacturer’s instructions. Direct sequencing was preferred for the amplicons with two exons (because of the size) and for the PCR fragments with frequent polymorphisms. The same conditions were used to amplify the two INSL3 exons with the primers listed in Table 1.
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Comparative molecular modeling analysis was performed with the SWISS-MODEL and the Swiss-Pdb Viewer (28). For LGR8/GREAT we used the PDB-Brookhaven crystal structure coordinates of internalin (1D0B) (29), porcine ribonuclease inhibitor (2BNH) (30), and von Willebrand factor-binding domain of glycoprotein Ib 
(1M0Z) (31) as structural references. For INSL3 we used insulin (1G7A) (32) and Cdk6-P16Ink4A tumor suppressor complex (1BI7) (33), suggested by the program 3D-PSSM (34) as a folding cognate protein, as possible protein model candidates. Other templates, such as relaxin and IGF, did not produce enough data to be analyzed due to the short stretch of amino acids present in these structures. Evaluation of the structures obtained was performed with the programs WHAT IF (35), PROSITE (36), and SAPS (37).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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, bilateral FNAC of patients affected by azoospermia or severe oligozoospermia (29 with bilateral and 20 with unilateral cryptorchidism) showed Sertoli cell-only syndrome (SCOS; complete absence of germ cells) or bilateral severe hypospermatogenesis (strong reduction of germ cells),respectively. These patients can therefore be classified as severe bilateral testiculopathy, and this means, therefore, that in unilateral cryptorchid subjects the normally descended testis was damaged like the ex-cryptorchid one. Among patients with unilateral cryptorchidism and mild oligozoospermia, six of 11 (13.0%) showed SCOS or severe hypospermatogenesis in the ex-cryptorchid testis, but normal spermatogenesis in the contralateral testis. As discussed below, four patients were found to carry INSL3 mutations, and four had LGR8/GREAT mutations (8 of 87, 9.2%).
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Mutation analysis of the INSL3 gene identified three common polymorphisms in both cryptorchid and control subjects: L9L (27G
A), in 3% of cryptorchid men and 5% of controls, A60T (178GA) in 42.5% of cryptorchid men and 47% of controls, and L42L (126GA) in 57% of cryptorchid men and 58% of controls. On the contrary, three nucleotide substitutions (278CT, 304CT, and 305GA) leading to amino acid change (respectively, P93L, R102C, and R102H) were found in the heterozygous condition in four cryptorchid men (4 of 87, 4.6%). These three mutations were not found in any of the 80 controls. Furthermore, no mutations were found in a cohort of 150 noncryptorchid infertile men.
R102H was found in two subjects (no. 1440 and O-58) classified as bilateral cryptorchidism with bilateral severe testiculopathy. In particular (Table 3), patient 1440 underwent bilateral orchidopexy at 1 yr of age, a second surgery at 5 yr and still the right testis is located at the edge of the inguinal canal. He also reported a bilateral testicular trauma at 15 yr and was affected by left varicocele. His testiculopathy could, therefore, have different causes. Patient no. O-58 underwent bilateral orchidopexy at 6 and 11 yr of age. Seminal analysis showed in both patients severe oligozoospermia (sperm count, <0.5 million/ml) with a testicular cytological analysis resembling severe hypospermatogenesis. This bilateral severe testiculopathy involving only the spermatogenic component was in accordance with plasma concentrations of gonadal hormones, which showed high FSH levels with normal LH and testosterone. No other cases of cryptorchidism were present in their family, and no blood samples were available for relatives of these subjects. R102H has previously been reported only in a female control (20), with apparently no phenotypic effect, but our findings suggest a role for this mutation in testis descent.
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P93L was found in a patient (no. 1372) affected by unilateral cryptorchidism who underwent orchidectomy of the undescended testis at 9 yr of age because of atrophy. Seminal analysis repeatedly revealed normozoospermia, and hormonal concentrations were all in the normal range. Analysis of the parents’ DNA showed in the mother the same P93L mutation that, like R102C, had no phenotypic effect. He has a paternal cousin affected by bilateral cryptorchidism, but a DNA sample was not available for analysis.
In the putative protein model the amino acid R102 is within a long coil, whereas P93 is inside an -helix, in agreement with data obtained from the secondary structure prediction programs. No variations from the secondary structure prediction was observed for the mutated R102C/H proteins compared with the native protein. However, protein analysis revealed that the segment encompassing the region of R102 is exhibiting a relatively high charge concentration centered precisely in amino acid R102. This behavior is lost in both mutated proteins R102C and R102H. No new disulfide bonds with other cysteins are predicted to exist. Analysis of the amino acid stretch QPLPQ containing P93 revealed that it is quite conserved among different species. The mutant P93L shows an evident secondary structure rearrangement in the amino acids preceding the mutation. Thus, the mutation seems to determine a sterical problem in the protein causing a loss of an entire -helix.
LGR8/GREAT mutations
The LGR8/GREAT mutation analysis identified one deleterious mutation (in heterozygosity), T222P, in four patients. This missense mutation has been described in one patient among 60 subjects affected by cryptorchidism (16) and was never found in controls from different regions (193 in the Gorlov’s study and 80 in the present study). The four subjects with the T222P mutation have different phenotypes (Table 3
). One patient (no. 466) was affected by bilateral cryptorchidism orchidopexied at 26 yr of age, and he has bilateral severe testiculopathy with very small testicles, azoospermia, high FSH with normal LH and testosterone plasma levels, and bilateral Sertoli cell-only syndrome, with few loci of severe hypospermatogenesis. Two patients (no. B77 and B85) were affected by unilateral cryptorchidism. In one case (patient B77) the right testis spontaneously descended in the scrotum at 13 yr, he was affected by mild oligozoospermia, hormonal levels were in the normal range, and FNAC showed SCOS in the ex-cryptorchid testis and only mild hypospermatogenesis in the contralateral testis that presented an important varicocele. Correction of varicocele led to an improvement of seminal parameters, and the patient become a father naturally. The other patient (patient B85) underwent left orchidopexy at 4 yr of age and repeatedly presented normozoospermia, with normal plasma concentrations of gonadal hormones. Analysis of the parents’ DNA showed in the mother the same T222P mutation in the heterozygous condition that, like INSL3 mutations, had no phenotypic effect. He has a nephew (son of his sister) affected by right cryptorchidism, but a DNA sample was not available for analysis. The last patient (no. 1030) experienced bilateral cryptorchidism at birth with spontaneous descent during puberty, and at present his testes are retractile. He shows severe oligozoospermia with a bilateral severe hypospermatogenesis and high FSH levels.
The analysis of a protein model reveals that in the T222P mutation the introduced proline seems to cause possible bending or kinking problems to the adjacent secondary structure elements, determining some locally protein structure instabilities. This is also confirmed by a secondary structure prediction database (PSIpred) (38). The amino acid T222 is conserved within the LRR domain and seems to be one of the amino acids important for determining the consensus of the domain as LRR. Therefore, T222 appears to be a possible key residue for the activity role of the protein, and alteration of one of these units probably is the cause of the reduction in protein binding strength. The introduction of a proline at position 222 cannot determine a big change in structure, and therefore, the mutations seems to influence only the folding of the LRR in which it is located.
Several polymorphisms in LGR8/GREAT exonic and intronic sequences were identified in patients and controls (Table 4), including a stretch of adenine at the intron 12-exon 12 junction that was shown to be polymorphic in length, varying from 9–13. Analysis of exon 12 and intron 12 polymorphisms allowed us to discriminate six different haplotypes (Table 4), whose frequency was not different between controls and cryptorchid subjects. It is worth noting that all patients with the LGR8/GREAT T222P mutation show haplotype GA13, suggesting that T222P occurred once on the chromosome bearing the GA13 haplotype. According to this hypothesis a founder effect could be present, and all patients in our group might share a common ancestor.
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Discussion |
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Insl3 and Lgr8/Great knockout mice are very important animal models, above all because they represent the first description of a specific mutation causing cryptorchidism as the only phenotype. Both Insl3 and Lgr8/Great homozygotes male mice show the same cryptorchid phenotype due to failure of gubernaculum differentiation (10, 11, 15, 16, 42). Interestingly, the mice show absence of spermatogenesis, but surgically descended testes have normal spermatogenesis (16), suggesting that the mutation impairs only testicular descent without directly affecting testis function, whose alteration would be the result of the testis malposition. This was confirmed by the finding that in Inls3 knockout mice orchidopexy can rescue the cryptorchid testes from their fate of Sertoli cell-only syndrome and lead to fertility (43). Our results seem to support this hypothesis. We found a high incidence of INSL3-LGR8/GREAT mutation in cryptorchid patients (9.2%), showing that the clinical consequence of alterations of this system seems to be failure of the testis to correctly descend in the scrotum without apparently affecting the spermatogenic and endocrine components of the testis itself. In fact, INSL3 and LGR8/GREAT mutations could be associated with different seminal patterns, including normozoospermia, and are compatible with fertility, and the eventual damage of tubular function (up to Sertoli cell-only syndrome) seems to be secondary to the abnormal position of the testis or other causes (surgical trauma, varicocele, etc.). Therefore, the timing of orchidopexy is crucial for the phenotype of cryptorchid testes in the adult. It is important to note that the phenotype of subjects with INSL3-LGR8/GREAT mutations may vary from bilateral cryptorchidism, to unilateral maldescent, to spontaneous descent of the testes after birth with subsequent retractile testes. All of these phenotypes agree well with an alteration of gubernaculum development. Although INSL3 is expressed in the steroidogenic Leydig cells, and LGR8/GREAT too is expressed in testis, the endocrine function of the testis of subjects with the INSL3-LGR8/GREAT mutation is not damaged, as documented by normal LH, testosterone, and (when available) inhibin B plasma concentrations.
All of the INSL3 or LGR8/GREAT mutations we found were heterozygous. We have never found homozygous mutations, nor have we found patients with two mutant alleles or patients compound heterozygote for mutations in LGR8/GREAT and INSL3. This is in contrast to that observed in mice, where homozygotes knockout mice are cryptorchid, but heterozygotes are normal. There are several hypotheses to explain how these heterozygote mutations might be responsible for causing cryptorchidism. Mutations may be dominant negative characters where the mutated allele may compete with the wild type for the ligand/receptor. This could explain the difference between humans and knockout mice, as in heterozygous male mice, one allele is completely missing. It is possible that another unidentified mutation is present (for example, in the promoter region), but no heterozygous mutation has been never found in unaffected controls (9, 16, 18, 19, 20, 21, 22, 23, 24, 25). Another hypothesis is related to haploinsufficiency, where a threshold effect exists, and the absence of one allele is enough to cause the phenotype. In the three cases (two INSL3 and one LGR8/GREAT) in which parent’s DNA was available, we found that the mutation was transmitted from the mothers, who have no phenotypic abnormalities. This is in agreement with that found in mouse, where homozygous Great(Lgr8)-/- or Insl3-/- females seem to be normal (16). Therefore, in humans, as in mice, female carriers are normal. The finding that mutations seems to be maternally inherited allows us to suppose that these genes are subject to imprinting, so that only the maternal allele is expressed. However, in the genomic regions where INSL3 and LGR8/GREAT map, no imprinted gene is described. Another very remote possibility is that the mutations are activating and somehow interfere with normal INSL3 action. We also have to consider that other factors (genetic or environmental) may contribute to the phenotype, and this may explain why identical mutations were associated with varying phenotypes. This is particularly evident for LGR8/GREAT, where the same T222P mutation is found in four patients completely different one from the other. The last hypothesis is that the mutations detected are not associated with the cryptorchid phenotype, but represent a fortuitous finding. However, there are several elements supporting a pathogenetic role of these mutations. Firstly, adding the results of the present study with those of all previous published studies, these mutations have never been found in control subjects (almost 600 controls for INSL3 and almost 200 controls for LGR8/GREAT) (9, 16, 18, 19, 20, 21, 22, 23, 24, 25). Secondly, in transfection assays the LGR8 T222P mutation has been shown to be unable to mediate relaxin-induced cAMP production (16). Finally, molecular modeling and comparative analyses of protein sequences revealed the importance of the mutated amino acids.
In fact, results from the present and previous works revealed two important residues in the INSL3 amino acid sequence (93 and 102) and only one in the LGR8/GREAT sequence (222). The mechanisms by which mutations of these residues alter protein function are hypothetical and different. The arginine at position 102 in INSL3 is the fourth before last of the C peptide, and it belongs to a conserved stretch of positively charged amino acids near the cleavage site between C peptide and A chain. Molecular modeling structure analysis revealed that R102C and R102H mutations do not determine structural changes, but an alteration of a charged zone of the protein. It is possible that the change in the amino acid sequence surrounding the cleavage site might abolish the processing of C peptide that will not be excised. Such protein will possibly not be able to stimulate its receptor (44). Proline 93 is part of a conserved specular sequence, QPLPQ, of C peptide, and P93L causes evident secondary structure rearrangement with loss of an entire -helix and therefore protein instability. Further functional analyses are in progress to assess the pathogenetic mechanism of INSL3 mutations. On the contrary, in vitro functional analysis of the T222P substitution has been already performed (16). Our analysis of putative protein model confirmed these results, showing that the T222P missense substitution causes a structural reorganization with partial unfolding in the fourth LRR and subsequent reduction in protein binding strength. The partial unfolding of this region is in agreement with clinical data and with the variable penetrance encountered.
In conclusion, our data demonstrate that cryptorchidism may frequently be associated with mutations in INSL3 and its receptor LGR8/GREAT. These genes seem to have an important role in testicular descent without apparently affecting the spermatogenic and endocrine components of the testis itself. Further studies would clarify the molecular events involved in INSL3-LGR8/GREAT interaction as well as possible interaction with other factors implicated in testicular descent.
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Acknowledgments |
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Footnotes |
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Abbreviations: CSL, Cranial suspensory ligament; FNAC, fine needle aspiration cytology; Insl3, insulin-like factor 3; MIS, Mullerian inhibiting substance; SCOS, Sertoli cell-only syndrome.
Received February 28, 2003.
Accepted May 28, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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and its complex with von Willebrand factor A1 domain. Science 297:1176This article has been cited by other articles:
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  A. Ferlin, D. Zuccarello, B. Zuccarello, M. R. Chirico, G. F. Zanon, and C. Foresta Genetic Alterations Associated With Cryptorchidism JAMA, November 19, 2008; 300(19): 2271 - 2276. [Abstract] [Full Text] [PDF]
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 C. Foresta, D. Zuccarello, A. Garolla, and A. Ferlin Role of Hormones, Genes, and Environment in Human Cryptorchidism Endocr. Rev., August 1, 2008; 29(5): 560 - 580. [Abstract] [Full Text] [PDF]
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 F. Nuti, E. Marinari, E. Erdei, M. El-Hamshari, M. G. Echavarria, E. Ars, G. Balercia, M. Merksz, C. Giachini, K. Z. M. Shaeer, et al. The Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 8 Gene T222P Mutation Does Not Cause Cryptorchidism J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 1072 - 1076. [Abstract] [Full Text] [PDF]
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 H.E. Virtanen and J. Toppari Epidemiology and pathogenesis of cryptorchidism Hum. Reprod. Update, January 1, 2008; 14(1): 49 - 58. [Abstract] [Full Text] [PDF]
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 C. R. Cederroth, O. Schaad, P. Descombes, P. Chambon, J.-D. Vassalli, and S. Nef Estrogen Receptor {alpha} Is a Major Contributor to Estrogen-Mediated Fetal Testis Dysgenesis and Cryptorchidism Endocrinology, November 1, 2007; 148(11): 5507 - 5519. [Abstract] [Full Text] [PDF]
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 N. V. Bogatcheva, A. Ferlin, S. Feng, A. Truong, L. Gianesello, C. Foresta, and A. I. Agoulnik T222P mutation of the insulin-like 3 hormone receptor LGR8 is associated with testicular maldescent and hinders receptor expression on the cell surface membrane Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E138 - E144. [Abstract] [Full Text] [PDF]
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A. Ferlin, A. Garolla, F. Rigon, L. Rasi Caldogno, A. Lenzi, and C. Foresta Changes in Serum Insulin-Like Factor 3 during Normal Male Puberty J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3426 - 3431. [Abstract] [Full Text] [PDF]
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 A. Ferlin, N.V. Bogatcheva, L. Gianesello, A. Pepe, C. Vinanzi, A.I. Agoulnik, and C. Foresta Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization Mol. Hum. Reprod., June 1, 2006; 12(6): 401 - 406. [Abstract] [Full Text] [PDF]
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E. Rajpert-De Meyts Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects Hum. Reprod. Update, May 1, 2006; 12(3): 303 - 323. [Abstract] [Full Text] [PDF]
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F.P. Yuan, D.X. Lin, C.V. Rao, and Z.M. Lei Cryptorchidism in LhrKO animals and the effect of testosterone-replacement therapy Hum. Reprod., April 1, 2006; 21(4): 936 - 942. [Abstract] [Full Text] [PDF]
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 C. Staub, M. Rauch, F. Ferriere, M. Trepos, I. Dorval-Coiffec, P. T. Saunders, G. Cobellis, G. Flouriot, C. Saligaut, and B. Jegou Expression of Estrogen Receptor ESR1 and Its 46-kDa Variant in the Gubernaculum Testis Biol Reprod, October 1, 2005; 73(4): 703 - 712. [Abstract] [Full Text] [PDF]
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M. Muda, C. He, P. G.V. Martini, T. Ferraro, S. Layfield, D. Taylor, C. Chevrier, R. Schweickhardt, C. Kelton, P. L. Ryan, et al. Splice variants of the relaxin and INSL3 receptors reveal unanticipated molecular complexity Mol. Hum. Reprod., August 1, 2005; 11(8): 591 - 600. [Abstract] [Full Text] [PDF]
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C. Foresta, A. Bettella, C. Vinanzi, P. Dabrilli, M. C. Meriggiola, A. Garolla, and A. Ferlin A Novel Circulating Hormone of Testis Origin in Humans J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 5952 - 5958. [Abstract] [Full Text] [PDF]
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E. L. Aschim, A. Nordenskjold, A. Giwercman, K. B. Lundin, Y. Ruhayel, T. B. Haugen, T. Grotmol, and Y. L. Giwercman Linkage between Cryptorchidism, Hypospadias, and GGN Repeat Length in the Androgen Receptor Gene J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5105 - 5109. [Abstract] [Full Text] [PDF]
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