Dissociated tubular-interstitial testicular dysfunction in a patient with McCune-Albright syndrome: pathogenic mechanism

REY, R.; COUTANT, R.; VENARA,M.; TRABUT, J.; ROULEAU, S.; PICARD, J.Y.; LIMAL, J.; SULTAN, C.; LUMBROSO, S.

Lyon, Francia

Congreso; Lawson Wilkins Pediatric Endocrinology Society / European Society for Pediatric Endocrinology 2009 Meeting; 2005

McCune-Albright syndrome is classically characterized by polyostotic fibrous dysplasia, café-au-lait skin lesions, and gonadotropin-independent gonadal activation (in boys, pseudo-precocious puberty with testis enlargement and elevated testosterone). Somatic gain of function mutations in the Gsa protein gene have been found in affected tissues. In the testis, Gsa is involved in signal transduction of gonadotropins: LH in interstitial Leydig cells and FSH in seminiferous tubule Sertoli cells. We previously reported a 3 yr-old boy presenting with macro-orchidism, high serum levels of Sertoli cell markers anti-Müllerian hormone (AMH) and inhibin B, but low testosterone. The patient’s parents had given informed consent for the study. Testicular biopsy showed Sertoli cell hyperplasia with otherwise prepubertal features. A somatic R201H mutation was detected in the Gsa protein gene in DNA extracted from testis. We aimed at understanding why only Sertoli cells showed hyperactivity, whereas Leydig cells remained quiescent. We performed laser capture microdissection of testicular paraffin-embedded tissue in order to selectively isolate seminiferous tubules from interstitial tissue. DNA extracted from the different compartments was screened for R201H mutation by direct sequencing of PCR products obtained by nested PCR. Only DNA from seminiferous tubules displayed the mutation. Further, we compared the trans-activating capacity of a normal and a R201H Gsa on the human AMH promoter activity in transient transfection assays. AMH promoter activity, evaluated by luciferase assay, was significantly higher (p<0.05) after transfection of R201H-Gsa (3.7 ± 0.9 relative luciferase units) than of wild-type Gsa (2.1 ± 0.7 relative luciferase units). We conclude that a somatic mutation R201H probably occurring in the Gsa protein gene before testicular cell lineages differentiation in early embryonic life affected Sertoli but not Leydig cell precursors. The mosaic mutation, which mimicked the effect of FSH, resulted in isolated Sertoli cell activation evidenced by hyperplasia leading to prepubertal macro-orchidism and elevated AMH production, with no signs of Leydig cell activation.