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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 10 3803-3806
Copyright © 1999 by The Endocrine Society

Original Studies

Evidence for Genetic Heterogeneity in Male Pseudohermaphroditism due to Leydig Cell Hypoplasia1

Juan Carlos Zenteno2, Patricia Canto, Susana Kofman-Alfaro and Juan Pablo Mendez

Research Unit in Developmental Biology, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (J.C.Z., P.C., J.P.M.); and the Department of Genetics, Hospital General de México, Secretaría de Salud, Faculty of Medicine, Universidad Nacional Autónoma de México (J.C.Z., S.K.-A.), Mexico, D.F., Mexico

Address all correspondence and requests for reprints to: Juan Pablo Méndez, M.D., Coordinación de Investigación Médica, Unidad de Investigación Médica en Biología del Desarrollo, Avenida Cuauhtémoc 330, Apartado Postal 73–032, Colonia Doctores, C.P. 06725, Mexico, D.F., Mexico. E-mail: jpmb{at}servidor.unam.mx


   Abstract
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 Abstract
Subjects and Methods
 Results
 Discussion
 References
 
Leydig cell aplasia or hypoplasia is a rare form of male pseudohermaphroditism resulting from inadequate fetal testicular Leydig cell differentiation. Affected individuals presented a wide phenotypic spectrum, ranging from complete female external genitalia to males with micropenis. Recessive mutations in the LH receptor gene have been identified as responsible for the condition. The majority of these mutations are point mutations and have been located in exon 11 of the gene. In this study, we report the molecular characterization of the LH receptor gene in three siblings with Leydig cell hypoplasia. After sequencing the 11 exons of the gene, no deleterious mutations were detected in any patient. However, we identified a previously described polymorphism in exon 11. In patients 1 and 3 DNA sequencing revealed a C to T substitution at nucleotide 1065; both patients were homozygous GAT/GAT at codon 355. In contrast, patient 2 was homozygous GAC/GAC, whereas the father and one unaffected sister were heterozygous GAC/GAT at this polymorphic site. These results exclude that Leydig cell hypoplasia in this family is due to a mutation in the LH receptor gene and provide evidence that defects in other loci may also result in failure of Leydig cell differentiation, demonstrating, for the first time, that Leydig cell hypoplasia is a genetically heterogeneous condition. . Subsequently, male phenotypic development is under the control of three fetal hormones that exert their effects on the genital primordium. The first event is Mullerian duct regression, which depends on the effect of the Sertoli cell-synthesized Mullerian inhibiting hormone. Immediately thereafter, testosterone (synthesized in Leydig cells) stimulates Wolffian duct proliferation while 5{alpha}-dihydrotestosterone (synthesized at the target cell level) virilizes external genitalia. Fetal Leydig cell differentiation and testosterone synthesis occur in a similar fashion as in the adult; however, as fetal LH is not yet available at this point in time, trophoblastically produced hCG takes over the LH actions. hCG/LH requires the presence of membrane-located hCG/LH receptors in Leydig cells (2).

Male pseudohermaphroditism (MPH) encompasses a group of disorders that can arise from a variety of conditions, including abnormalities of androgen end-organ response, enzymatic defects in androgen bioynthesis, defective Mullerian duct regression, and abnormal testicular differentiation. Leydig cell agenesis or hypoplasia, which has an autosomal recessive inheritance pattern, is a well defined form of MPH resulting from inadequate fetal testicular Leydig cell differentiation (3–14). Individuals with this condition exhibit a wide clinical spectrum that ranges from phenotypic females to males with micropenis (14, 15). Mullerian derivatives are always absent, and vas deferens with epididymis are occasionally found (3, 4, 6, 9). The hormonal profile in these patients is characterized by low levels of serum testosterone (basal and hCG-stimulated) and elevated levels of LH (16).

Recently, a number of mutations in the LH receptor gene have been characterized in familial and sporadic cases of Leydig cell agenesis or hypoplasia (17–26). The majority of these mutations were found in affected homozygotes, although compound heterozygosity has been identified in two cases (20, 23). In vitro expression studies of the mutated receptors demonstrated impaired or absent ligand binding and cAMP production in response to hCG stimulation, confirming the inactivating effect of these mutations in LH receptor activity (17–26).

Here we report the molecular findings regarding the LH receptor gene in a familial case of MPH due to Leydig cell hypoplasia. Our data exclude that mutations in the LH receptor gene are the cause of this disorder in this particular family and demonstrate, for the first time, that Leydig cell hypoplasia is a genetically heterogeneous condition.


   Subjects and Methods
Top
 Abstract
 Subjects and Methods
Results
 Discussion
 References
 
A nonconsanguineous Mexican family with three affected individuals was studied. The propositus was an 18-yr-old phenotypical woman (II-2) who was referred to our hospital because of primary amenorrhea and absence of sexual development. Two other affected patients (II-3 and II-4), 26 and 8 yr old, were also studied (Fig. 1Go).



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  		Figure 1. Pedigree of the family with MPH due to Leydig cell hypoplasia.

 
Both adult patients presented with primary amenorrhea, absence of secondary sexual characteristics, intraabdominal testes, and a 46,XY karyotype in blood leukocytes. Concentrations of serum LH and FSH were elevated, whereas basal and hCG-stimulated levels of testosterone were extremely low. Testicular histological examination in both siblings revealed seminiferous tubules lined by Sertoli cells and absence of mature interstitial Leydig cells. However, small randomly distributed nodules of mature Leydig cells without crystalloids were also observed. No changes in interstitial cell morphology were induced after hCG administration. The youngest sister presented with a left inguinal mass and a 46,XY karyotype. The detailed clinical, endocrinological, and histological features of all three patients were reported previously (5). A 20-yr-old affected sibling who had died before the family was studied, had a history of primary amenorrhea, lack of breast enlargement, and absence of sexual hair growth. Three sisters with normal sexual development (II-5–7) had no history of amenorrhea or oligomenorrhea. Informed consent was obtained from all subjects participating in the study.

Methods

Genomic DNA from the three patients, their father, and one unaffected sister was prepared from peripheral blood leukocytes using standard techniques (27). For each PCR amplification, genomic DNA (0.5–1.0 µg) in the presence of 0.1 mmol/L deoxy-NTP, 2 U Taq DNA polymerase (Amplitaq, Perkin Elmer Corp., Branchburg, NJ), and 250 nmol/L of each specific set of primers were used. The sequences of the primers, the sizes of the amplified products, as well as the PCR conditions were previously described by Atger et al. (28). Due to the high G-C content of exon 1, 5% dimethylsulfoxide was added to the PCR reaction for amplifying this exon. Thirty cycles of PCR amplifications were performed in a thermal cycler with denaturation at 94 C for 30 s, annealing at the temperature and duration previously described (28), and extension at 72 C for 1 min. The final extension cycle was 72 C for 7 min.

Amplified PCR products of the 11 exons of the LH receptor gene were isolated after agarose gel electrophoresis and then purified by GeneClean (BIO-101, Vista, CA). These products were then sequenced using 300 nmol DNA template/reaction on an ABI 373 automated DNA sequencer (Perkin Elmer Corp., PE Applied Biosystems, Foster City, CA) using the dye terminator cycle sequencing core kit (Perkin Elmer Corp.). PCR conditions for cycle sequencing were identical to those used for the initial PCR amplification. For all exons, both strands were sequenced and compared. Sequence variations were confirmed performing two independent PCR amplifications and sequencings.


   Results
Top
 Abstract
 Subjects and Methods
 Results
Discussion
 References
 
No gross deletions or insertions were detected after PCR amplification of the 11 exons of the gene in any of the 5 individuals studied. In patients 1 and 3 DNA sequencing revealed a C to T substitution at nucleotide 1065; both patients were homozygous GAT/GAT at codon 355 in exon 11. However, this mutation did not change the encoded amino acid (aspartic acid). In contrast, patient 2 was homozygous GAC/GAC, whereas the father and unaffected sister were C/T heterozygous, GAC/GAT, at this polymorphic site of the gene (Fig. 2Go). In addition, 6 normal individuals used as controls were homozygous GAC/GAC, and 4 others presented GAC/GAT heterozygosity at codon 355.



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  		Figure 2. Automated sequence analysis from part of exon 11 of the LH receptor gene. Patients 1 (II-2) and 3 (II-4) were T homozygous for the C1065T polymorphism; patient 2 (II-3) was C homozygous; the father (I-1) and an unaffected sister (II-5) were C/T heterozygous.

 
Sequence analysis of exon 1 showed that all five individuals from the affected family presented homozygosity for the {alpha}LQ variant of the LH receptor. Ten normal individuals used as controls were also homozygous for the {alpha}LQ allelic variant of the protein.

No other changes were detected in the nucleotide sequence of the remaining exons of the gene in any of our patients.


   Discussion
Top
 Abstract
 Subjects and Methods
 Results
 Discussion
References
 
Defects in the LH receptor gene result in abnormal Leydig cell differentiation and function during embryogenesis in affected 46,XY patients. Inadequate testosterone and consequently dihydrotestosterone production results in the development of abnormal male external genitalia. The phenotypes of these subjects are variable, ranging from phenotypic females to males with micropenis. These phenotypic diversities can be explained at least in part by the various defects of the LH receptor gene. It has been demonstrated that different mutations in the gene can cause either complete or partial loss of LH receptor function (17, 18, 19, 20, 21, 22, 23, 24, 25, 26).

In this study we report the molecular analysis of the LH receptor gene in 3 siblings with MPH due to Leydig cell hypoplasia. After sequencing the 11 exons of the gene, we were unable to identify deleterious mutations in any of the patients. However, we detected a previously described polymorphism in exon 11 at position 1065 (29). This C/T polymorphism, located at codon 355, did not change the encoded amino acid (aspartic acid). The polymorphism was informative in this family: patients 1 and 3 were homozygous GAT/GAT, patient 2 was homozygous GAC/GAC, and the father as well as the healthy sister were heterozygous GAC/GAT at this polymorphic site. The deduced genotype of the deceased mother was GAC/GAT. The segregation of this polymorphism excludes the possibility that a mutation of the LH receptor gene was responsible for the Leydig cell hypoplasia phenotype observed in the three affected siblings. Although Chan (30) recently reported some undescribed Leydig cell hypoplasia families who apparently had no mutations in the LH receptor gene, to our knowledge our family constitutes the first report in which a mutation of the LH receptor gene can conclusively be excluded as responsible for this disease. The segregation of the informative C1065T polymorphism in this family also excludes, beyond any reasonable doubt, the presence of deleterious mutations in the noncoding regions of the gene as being responsible for the pathogenesis of Leydig cell hypoplasia.

Although our three patients exhibited most of the clinical and histological features described in cases of Leydig cell hypoplasia, some differences were observed. In patients 1 and 2, besides the Leydig cell hypoplasia identified in most of the interstitium, there were small nodules of mature Leydig cells without crystalloids; in addition, a rudimentary portion of the left Fallopian tube was recognized in patient 1 (5). These phenotypic differences could reflect a distinct pathogenic mechanism leading to the disease. Our results indicate that Leydig cell hypoplasia is a genetically heterogeneous condition and that mutations in another gene(s) can also cause failure of Leydig cell differentiation. Leydig cell agenesis has been reported occasionally in sex chromosome aberrations (31, 32, 33), suggesting the involvement of several loci in the development of this testicular cell type. In fact, in our family we can not exclude X-linked recessive inheritance.

There is evidence that Leydig cell differentiation involves a complex, yet undefined, signaling pathway where several genes can participate as has been demonstrated by various studies. In hypophysectomized rats, 2 days after administration of the cytotoxic agent ethane dimethyl sulfonate, a 6-fold increment in the proliferative activity of Leydig cell precursors has been observed (34). This suggests that other factors, different from LH, act locally, stimulating the proliferation of precursor cells after ethane dimethyl sulfonate administration. Moreover, Nalbant et al. (35) demonstrated that the CCAAT/enhancer binding-protein-ß plays a significant role in LH-regulated Leydig cell differentiation and function. Mutations in any of these genes could explain the phenotype observed in our family.

On the other hand, all subjects tested in this study presented the {alpha}LQ allelic variant of the LH receptor. This variant lacks a two-amino acid insertion (Leu-Gln) at residues 19 and 20 that is present in the LQ variant of the protein, which is commonly observed in Caucasians (36). Interestingly, Rodien et al. (36) never found the LQ allele in a population of 110 Japanese subjects, and although our sample is small (30 chromosomes), the similarity with our population could reflect the geographical dispersal of ancestral human populations (37).

In conclusion, our results demonstrate that the MPH due to Leydig cell hypoplasia in the three siblings studied cannot be attributed to a molecular defect in the LH receptor gene, evidencing the genetic heterogeneity of this rare condition. The characterization of Leydig cell-specific genes involved in Leydig cell differentiation could offer an explanation for those cases of Leydig cell agenesis or hypoplasia in which no mutations of the LH receptor gene are detected.


   Footnotes
 
1 This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico (Grants G28494M and G29790M). Back

2 Postgraduate student supported by a CONACYT fellowship award. Back

Received April 9, 1999.

Revised July 21, 1999.

Accepted July 27, 1999.


   References
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 Subjects and Methods
 Results
 Discussion
 References
 

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