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Human Molecular Genetics Advance Access originally published online on November 13, 2006
Human Molecular Genetics 2006 15(24):3538-3543; doi:10.1093/hmg/ddl430
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Unexpected mosaicism of R201H-GNAS1 mutant-bearing cells in the testes underlie macro-orchidism without sexual precocity in McCune–Albright syndrome

Rodolfo A. Rey1,2,*, Marcela Venara1, Régis Coutant3, Jean-Baptiste Trabut4, Stéphanie Rouleau3, Najiba Lahlou5, Charles Sultan7, Jean-Marie Limal3, Jean-Yves Picard6 and Serge Lumbroso7,{dagger}

1 Centro de Investigaciones Endocrinológicas (CONICET), Hospital de Niños R. Gutiérrez, Buenos Aires, Argentina, 2 Departamento de Histología, Biología Celular, Embriología y Genética, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina, 3 Département de Pédiatrie and Centre de Référence des Pathologies Rares de la Réceptivité Hormonale, Centre Hospitalier Universitaire, Angers, France, 4 Carcinogenèse Hépatique et Virologie Moléculaire (INSERM), Faculté de Médecine Necker, Paris, France, 5 Laboratoire de Biologie Hormonale, Centre Hospitalier Universitaire Cochin—Saint Vincent de Paul, Paris, France, 6 Endocrinologie et Génétique du Développement et de la Reproduction (INSERM), Université Paris XI, Clamart, France; and 7 Laboratoire d'Hormonologie, Centre Hospitalier Universitaire de Montpellier and Endocrinologie Moléculaire et Cellulaire des Cancers (INSERM), Montpellier, France

* To whom correspondence should be addressed at: Centro de Investigaciones Endocrinológicas (CONICET), Hospital de Niños R. Gutiérrez, Gallo 1330, C1425EFD Buenos Aires, Argentina. Tel: +54 11 4963 5931 (ext. 125); Fax: +54 11 4963 5930; Email: rodolforey{at}cedie.org.ar

Received August 21, 2006; Accepted November 1, 2006


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
McCune–Albright syndrome (MAS), usually presenting with polyostotic bone dysplasia, café-au-lait skin lesions and sexual precocity, results from a somatic activating mutation of the GNAS1 gene, which encodes the Gs-alpha protein involved in signalling of several G-protein-coupled receptors. The clinical spectrum depends on tissue distribution of mutant-bearing cells. Sexual precocity has been ascribed to the occurrence of a mutant GNAS1 allele in the gonadal anlage, from which all somatic cells of the differentiated gonads arise. In boys, precocious activation of Leydig cell androgen secretion results in pubertal spermatogenesis, leading to testicular enlargement, and in the development of secondary sex characteristics. However, sexual precocity is rare in MAS males while isolated testicular enlargement is frequently observed. We recently reported the case of a boy with macro-orchidism and signs of Sertoli cell hyperactivity but no signs of hyperandrogenism, which was unexpected since Gs-alpha is functional in both Sertoli and Leydig cells. To understand its pathophysiology, we microdissected an available testicular biopsy to separate Sertoli from Leydig cells. The R201H-GNAS1 allele was present only in Sertoli cells, resulting in isolated Sertoli cell hyperfunction, evidenced by increased AMH expression and cell hyperplasia leading to prepubertal macro-orchidism, with no signs of Leydig cell activation. The different early embryologic origin of precursors contributing to Sertoli and Leydig cell lineages may underlie the differential existence of the mutated GNAS1 gene. Lack of occurrence of the mutation in Leydig cells may explain why sexual precocity is rarely observed in boys with MAS.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
McCune–Albright syndrome (MAS) [MIM 174800 [OMIM] ] results from a somatic activating mutation in the GNAS1 gene [MIM 139320 [OMIM] ], mapping on 20q13.2 and encoding the stimulatory guanine-nucleotide-binding protein (Gs protein) alpha-subunit (Gs-alpha). Gs-alpha is normally involved in the signalling pathway of several transmembrane receptors known as G-protein-coupled receptors (GPR) (1–3). Classical MAS presentation is defined by the triad of polyostotic fibrous dysplasia, café-au-lait skin lesions, and gonadotropin-independent gonadal precocious activation, although pituitary, thyroid or adrenal tumours and other non-endocrine abnormalities may also develop (2,3). MAS is generally not inherited, probably because germline Gs{alpha}-activating mutations are lethal. It is believed that the somatic mutation in MAS patients occurs early in development, and therefore the clinical spectrum in each individual is determined by the tissue distribution of mutant-bearing cells (reviewed in ref. 3). In bone, retraction of fibroblast cell body and consequent formation of pseudolacunar spaces result from increased cyclic AMP intracellular levels induced by the constitutively active Gs{alpha} protein. In skin, pigment granule formation is abnormally increased resulting in typical café-au-lait spots.

The pathophysiology of precocious activation of gonadal function in MAS patients may be explained by the fact that Gs{alpha} mediates the intracellular transduction pathways of the luteinizing hormone (LH) receptor—present in testicular Leydig cells and ovarian granulosa and theca cells—and the follicle-stimulating hormone (FSH) receptor—present in testicular Sertoli cells and ovarian granulosa cells. In normal childhood, endocrine gonadal activity is rather low owing to the negligible circulating LH and FSH levels. In the boy, testicular volume is mainly occupied by seminiferous tubules, containing Sertoli cells and few germ cells. Sertoli cells proliferate and secrete anti-Müllerian hormone (AMH) and inhibin B, and these activities can be enhanced by FSH (4,5). At puberty, LH rises and induces Leydig cells to secrete androgens. The increase in intratesticular testosterone levels provokes Sertoli cell maturation—characterized by a dramatic decline in their proliferating and AMH-secreting capacity (6)—and the onset of full spermatogenesis, responsible for the remarkable enlargement of testicular size, the hallmark of male pubertal onset. Peripheral androgen action results in the development of secondary male characteristics. MAS presents with sexual precocity when the mutated GNAS1 allele is present in gonadal tissue, since it provokes a constitutive activation of steroid hormone secretion in the child (7). However, two intriguing issues remain unexplained in the pathogenesis of precocious gonadal activation in MAS patients: sexual precocity is more frequently observed in girls than in boys (7), and testicular enlargement may not be associated with signs of peripheral hyperandrogenism (8–11).

Recently, we reported the case of a boy with MAS due to a typical R201H activating mutation (8). The 3-year-old patient had café-au-lait spots on the back and iliac and femoral bone fibrous dysplasia. Testicular volumes were 9 ml (right) and 7 ml (left). Contrasting with the pubertal volume of testes, the penis was infantile in size, and there was no pubic or axillary hair. LH, FSH and testosterone levels were in the prepubertal range. By contrast, serum levels of Sertoli cell markers –AMH and inhibin B–were elevated. A testicular biopsy obtained at 7 years showed prepubertal features: seminiferous tubules containing immature Sertoli cells, few spermatogonia and no meiotic germ cells, and an interstitial compartment with no Leydig cell maturation. Sequencing of the Gs{alpha} gene in DNA samples extracted from bone and gonadal tissue showed the presence of a guanine to adenine transversion leading to an Arg-His substitution at position 201 (R201H). Since Gs{alpha} is expressed in Leydig and Sertoli cells, both cell populations are assumed to be precociously activated in MAS patients with the GNAS1 mutation detected in DNA extracted from testicular biopsies. However, in our patient, testicular enlargement seemed associated with Sertoli but not Leydig cell hyperfunction. In order to understand why only Sertoli cells showed hyperactivity, we microdissected by laser capture seminiferous tubules from interstitial tissue of available testicular biopsy samples and extracted DNA separately from each testicular compartment to assess the presence of the mutation. Additionally, we examined the effect of the mutation on the relative composition of testicular compartments by stereological studies of the testicular biopsy and on Sertoli cell function by assessing the regulation of the AMH promoter activity in response to the mutated Gs{alpha} protein in cell culture.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Because testes only showed signs of Sertoli cells hyperactivity in our patient, we hypothesized that the Leydig cells did not carry the GNAS1 gene mutation detected in DNA extracted from whole testicular tissue (8). To test this hypothesis, we separated seminiferous tubules from interstitial tissue by laser capture microdissection and separately extracted DNA from each compartment in eight sections of three different areas of the biopsy (Fig. 1). Sequencing of the GNAS1 gene showed the presence of both the normal sequence and the R201H mutation in seminiferous tubules, whereas no mutated sequences were detected in interstitial tissue samples. These results indicate that there was a mosaicism of normal and abnormal cells, with the R201H-GNAS1 allele present in most Sertoli cells but not in Leydig cells or their precursors.


Figure 4301
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  		Figure 1. (A) Representative example of laser capture microdissection of a testis biopsy performed at the age of 7 years. Seminiferous tubules and interstitial tissue were microdissected on different caps, and enzymatic amplification was performed separately on each DNA sample. Representative sequences of the GNAS1 gene, encoding the Gs{alpha} protein, resulting from the analysis of DNA obtained from microdissected seminiferous tubules or interstitial tissue of top, middle and bottom samples of the testicular biopsy are shown. (B) Intracellular signal transduction mediated by Gs{alpha}. Under normal conditions, gonadotropins bind to their seven-transmembrane domain receptors coupled to G proteins consisting of alpha, beta and gamma subunits. The activation and release of Gs{alpha} subunit induces adenylyl cyclase (AC), which increases intracellular cyclic AMP (cAMP) levels, resulting in the activation of protein kinase A (PKA). In normal Sertoli cells, FSH regulates via this pathway cell proliferation and AMH expression. In normal Leydig cells, LH regulates cell proliferation and steroid synthesis. In Sertoli cells carrying the R201H mutation, the signalling pathway is constitutively active, resulting in abnormally increased cell proliferation and AMH expression.

 
To address the question of whether the presence of the mutation in Sertoli cells could be associated with testicular enlargement, we performed a quantitative histological analysis on eight sections of the testicular biopsy of our MAS patient and in six control biopsies obtained from age-matched boys. We observed an increase in the relative volume occupied by seminiferous tubules (MAS 72.1±6.9%, controls 40.3±3.1%, P=0.025) and in the total number of Sertoli cells/10 000 µm2 of testicular tissue (MAS 50.0±4.2, controls 22.3±5.0, P=0.007). These results indicate the existence of Sertoli cell hyperplasia, explaining testicular enlargement.

The effect of the R201H-Gs{alpha} protein on Sertoli cell endocrine activity was studied using a luciferase assay to assess changes in AMH promoter activity. SMAT1 cells, a murine prepubertal Sertoli cell line (12), were co-transfected with an AMH promoter-luciferase reporter plasmid and an expression vector containing the R201H-GNAS1 gene, the wild-type GNAS1 gene or no GNAS1 gene sequence. The normal Gs{alpha} protein enhanced the human AMH promoter activity, and the R201H-Gs{alpha} protein provoked a further stimulation (Fig. 2), suggesting that Sertoli cells carrying the mutation produce higher amounts of AMH.


Figure 4302
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  		Figure 2. Effect of R201H-Gs{alpha} on the activity of the AMH promoter. A clonal prepubertal Sertoli cell line (SMAT-1) (12) was transfected with either a pcDNA expression vector (top left), or a pcDNA expression vector containing the wild-type Gs{alpha} (top middle) or the R201-Gs{alpha} gene (top right), and co-transfected with a luciferase plasmid (luc) under control of 3063 bp of the human AMH promoter (5'-hAMH) (4). Results are expressed as mean±standard deviation of 3 different experiments and analyzed by ANOVA and Dunnett's multiple comparison post-test. *P<0.05; **P<0.01. A value of 1 corresponds to the basal 5'-hAMH-luc activity.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 REFERENCES
 
The pathophysiology of genetic disorders known to primarily affect only one cell population of a tissue or an organ can be explained by the fact that the mutated gene has no relevant function in the other cell populations. For instance in the testis, the LH receptor is only expressed in Leydig cells, and dissociated testicular dysfunction primarily affecting only Leydig cells results when the LH receptor gene is mutated (3,13). In MAS, it has been proposed that a somatic mutation occurring early in development would affect a certain number of organs according to the fate of the mutant-bearing pluripotent cells. Within this contextual concept, gonadal dysfunction has been believed to result from the existence of mutant somatic cells in which Gs{alpha} normally mediates functional activation, i.e. Sertoli and Leydig cells in the testis and granulosa and theca cells in the ovary. This hypothesis can explain sexual precocity observed in many MAS patients; however, it cannot justify the sex differences observed in the development of precocious gonadal activation (7) or the presentation with testicular enlargement not associated with precocious hyperandrogenism in a subset of MAS boys (8–11).

Here, we show that prepubertal macro-orchidism, with no signs of precocious androgen testicular production, can be explained by isolated Sertoli cell hyperplasia. According to the classical pathogenic hypothesis, this was unexpected in a MAS patient since the Gs{alpha} protein also activates Leydig cell function. Using laser capture to microdissect seminiferous tubules from interstitial tissue, we provide evidence for the molecular pathogenesis of this unexpectedly dissociated testicular dysfunction. The occurrence of the somatic gain-of-function R201H mutation in the GNAS1 gene exclusively in the seminiferous tubule compartment explains the coexistence of prepubertal Sertoli cell hyperactivity with Leydig cell quiescence observed in this patient. The occurrence of a mutated GNAS1 allele confined to the Sertoli cell population may not be an exception in MAS boys. This situation is probably overlooked owing to the lack of typical signs of androgen action, like the increase in penile size and the development of pubic hair, which call parents' attention more readily than a moderate increase in testicular size in a prepubertal boy. Although Sertoli cells represent the most conspicuous cell population of the prepubertal testis (14–17), their activity is barely noticeable unless meticulous physical examination or imaging of the gonads are performed, or circulating AMH (18,19) or inhibin B (20) levels are assessed. Recently, increased Sertoli cell proliferation, detected by the presence of small hyperechogenic foci in ultrasound imaging, was reported in two MAS patients with no sexual precocity (10). Another report describes a boy presenting with unilateral testis enlargement and no signs of androgen secretion, clearly indicative of the mosaic nature of the disorder not affecting Leydig cells (11). In a boy of prepubertal age, testicular enlargement not associated with signs of hyperandrogenism may represent an alarm sign of neoplasia, often requiring histopathological studies. In MAS patients, gonadal hyperactivation has not been reported to be followed by malignant transformation. Furthermore, at the onset of normal pubertal hypothalamic-pituitary activation, gonadotropins take over the control of gonadal activity and pregnancies have been described later in life in women with MAS diagnosed during childhood with peripheral precocious puberty due to autonomous ovarian cysts (21–23). Although data are still lacking to predict future reproductive function in male patients with Sertoli cell-limited MAS mutations in the gonads, conserved spermatogenesis could be expected if comparison with females is valid. Our patient is now 14 years-old and shows normal progression of puberty as assessed clinically (testicular volume 25 ml bilaterally, pubic hair stage 4) and biochemically (basal LH 1.1 IU/l peak LH to GnRH test 10.0 IU/l, basal FSH 2.2 IU/l, peak FSH to GnRH test 5.7 IU/l, testosterone 11.2 nmol/l, AMH 131 pmol/l, Inhibin B 100 pg/ml). This suggests that pubertal gonadotropins production overcame autonomous gonadal activity, and provoked an effective increase of intratesticular testosterone which induced an apparently normal Sertoli cell maturation, as denoted by the downregulation of AMH secretion and pubertal increase of testicular volume most probably due to spermatogenic onset (17,24).

An explanation for the mechanisms underlying the differential existence of the mutated GNAS1 gene in Sertoli and Leydig cells could rely on the embryologic origin of gonadal cell populations. In early embryogenesis, the epiblast differentiates into ectoderm, mesoderm and endoderm. The abdominal intermediate mesoderm originates the urogenital ridge, where the mesonephros is covered by coelomic epithelium. Although all somatic cells of the gonads arise from the urogenital ridge, Sertoli cells differentiate from coelomic epithelial cells (25), whereas Leydig cells derive from the mesonephros (26). In MAS, the postzygotic occurrence of an activating mutation in the GNAS1 gene leads to a mosaic distribution of mutant cells and to a variable constellation of abnormal tissues in each patient. It could be envisaged that the GNAS1 gene mutation occurs in one epiblast cell in early embryogenesis. This founder would give rise to a variable proportion of cells present in the presumptive territories that, during gastrulation, originate the different embryonic cell lineages (27). In our patient, the founder mutant epiblast cell might have originated a limited number of precursors present in the presumptive territories of the dorsal neural ectoderm responsible for the existence of café-au-lait spots on the back, and of the mesoderm differentiating into the coelomic epithelium responsible for the hyperactive Sertoli cells and into bone marrow stromal cells responsible for the bone dysplasia. Comparable to what we show in the testis, it is possible that a cellular mosaicism exists in skin and bone, regardless of whether their various tissue components have a similar origin.

Our findings may also give some insight into to the sexually dimorphic prevalence of precocious gonadal hyperactivity, which appears to be more frequent in MAS female patients (7). Both granulosa and theca cell populations of the ovary are steroidogenically competent, and the abnormal activation of any of them may result in a precocious increase of endocrine function. Conversely, in the male gonad, only Leydig cells are capable of androgen production. Therefore, MAS presents with precocious pubertal development in males only when Leydig cells carry the somatic activating mutation. It seems plausible that the incidence of gonadal affectation is the same in both sexes but that in boys, when only Sertoli cells carry the mutation, clinical manifestations of sexual precocity do not occur and the gonadal disorder is overlooked. We suggest that the more frequent report of gonadal hyperfunction in MAS girls may result from a case ascertainment bias, since obvious signs of precocious puberty in females are expected whenever granulosa or theca cells carry the mutation.

In summary, by using a novel diagnostic approach, we delineate the molecular and cellular mechanisms responsible for an unexpectedly dissociated organ dysfunction in MAS. We show that the existence of a known activating Gs{alpha} protein mutation with a mosaic pattern in the testis resulted in isolated Sertoli cell hyperfunction evidenced by elevated AMH production and cell hyperplasia leading to prepubertal macro-orchidism, with no signs of Leydig cell activation. Lack of occurrence of the mutation in Leydig cells may explain why sexual precocity is less frequently observed in boys with MAS. Since Sertoli cell-limited hyperplasia does not seem to be an unusual feature in boys with MAS and no increased risk of malignant evolution has been reported, testicular biopsy might not be necessary even in the event of focal hyperechogenic images observed in ultrasound examination of the testes. Data are still lacking to establish the reproductive function in adult life.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
REFERENCES
 
Morphometric analysis of testicular tissue
Quantitative histological analysis was performed, as previously described (28), on haematoxylin–eosin stained sections of a testicular biopsy obtained at the age of 7 years: two samples were taken from top of the biopsy, three from the middle and three from the bottom. A total surface of 65 000–70 000 µm2 was studied in each one of gonadal tissue areas. The relative volumes of testicular compartments (seminiferous tubules and interstitial tissue) were determined using a semiautomatic image analyzer (Optimas Corp., Bothell, WA) as described. The total number of Sertoli cell nuclei present in the analyzed areas was recorded. For comparison, the same procedure was performed using historical testicular biopsies obtained from six age-matched boys (ages: 5–8 years) with acute lymphoblastic leukaemia as a routine procedure to rule out gonadal invasion. All biopsies were diagnosed as normal prepubertal testes, with no lymphoblastic invasion. Results of the total number of Sertoli cells/10 000 µm2 of testicular tissue and of the relative area occupied by seminiferous tubules (seminiferous tubule area/total area of the biopsy sample analyzed) are expressed as mean±SD. Comparisons were made using an unpaired t test with Welch's correction.

Laser capture microdissection of testicular tissue
Testicular tissue sections from eight sections of the three different zones of the biopsy, contiguous to those used for the histological analysis, were submitted to laser capture microdissection to isolate the seminiferous tubules from the interstitial tissue, using a PixCell II instrument (Arcturus Engineering, Mountain View, CA) (29). Seminiferous tubules and interstitial tissue of each sampled area were microdissected on different caps (Fig. 1). After laser capture, caps were placed on 0.5 ml tubes and stored at –20°C until used as described (30).

Molecular analysis of GNAS1 gene
Enzymatic amplification was performed separately on each DNA sample extracted from seminiferous tubule and interstitial tissue of testicular biopsy areas. A method previously described for selective enrichment of mosaic R201H mutation of the GNAS1 gene was used (8). Sequencing reactions were performed twice with two different PCR products.

Effect of R201H-GS{alpha} on AMH promoter activity
Luciferase assays were performed as previously described (4) to evaluate the effect of the Gs{alpha} protein containing the R201H mutation on AMH promoter activity. SMAT1 cells, a prepubertal Sertoli cell line (12), were co-transfected with a luciferase expression plasmid under control of 3068 bp of the human AMH gene 5' region (-3068-5'hAMH-luc) (4) and a pcDNA expression plasmid either devoid of any encoding gene or containing the wild-type or the R201H-mutated Gs{alpha} gene (Interchim, Montluçon, France). Results are expressed as mean±SD of three different experiments and analyzed by ANOVA and Dunnett's multiple comparison post-test.

All statistical analyses were performed using GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, CA).

All procedures were performed following the ethical principles for medical research included in the World Medical Association Declaration of Helsinki and its amendments.


   ACKNOWLEDGEMENTS
 
R.A.R and M.V. are established staffs with the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. R.A.R. and J.Y.P. are recipients of a CONICET-INSERM bilateral cooperation agreement grant. R.A.R. is recipient of a PICT grant from the ANPCyT (Agencia Nacional de Promoción Científica y Tecnológica) and PIP grant from CONICET, Argentina.

Conflict of Interest statement. None declared.


   FOOTNOTES
 
{dagger} Present address: Laboratoire de Biochimie, Centre Hospitalier Universitaire, Nîmes, France. Back


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 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 

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