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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Unexpected mosaicism of R201H-GNAS1 mutant-bearing cells in the testes underlie macro-orchidism without sexual precocity in McCune–Albright syndrome
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
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.
Present address: Laboratoire de Biochimie, Centre Hospitalier Universitaire, Nîmes, France.
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