Disruption in SF1-Mediated AMH Promoter Regulation Leading to Persistent Müllerian Duct Syndrome (PMDS)

DI CLEMENTE N; JOSSO NATHALIE; MARSHALL I; REY RA; VALERI CLARA; SCHTEINGART HELENA F; PICARD JEAN-YVES

Buenos Aires

Congreso; XXVI Annual Meeting of the Latin American Pediatric Endocrinology Society (SLEP); 2016

SLEP

In early fetal life, AMH secreted by the testes provokes the regression of Müllerian ducts. AMH expression in fetal Sertoli cells is triggered by SOX9, and further up regulated by SF1, GATA4 and WT1, all binding to specific sites on the proximal AMH gene promoter. The absence of AMH signalling in the XY fetus results in the Persistent Müllerian duct syndrome (PMDS). We report the case of a non-dysmorphic newborn who presented with a normal sized penis and non-palpable gonads. Lab work-up showed normal serum testosterone (358 ng/dl), very low serum AMH (7.8 pmol/l) and a 46,XY karyotype. A sonogram and MRI showed a uterus measuring 5 x 1.4 x 1.9 cm; VCUG showed a normal male urethra without a urogenital sinus. DNA sequencing detected no mutations in the AMH gene coding sequences, but a homozygous single-base deletion (c.-225delA) was identified at a putative SF1 response element of the AMH promoter. The AMH promoter activity of the c.-225delA variant, analysed in luciferase assays, was decreased by 58 ± 14%, to a similar extent (66 ± 5%) of what was observed when the SF1 site was completely disrupted by in vitro directed mutagenesis. The interaction between SF1 and its binding site was lost when the oligonucleotide carried c.-225delA or the fully disrupted SF1 site, when studied by EMSA. In conclusion, the single base deletion c.-225delA within the SF1 site of the AMH gene promoter impaired SF1 binding to and transactivation of the AMH promoter, resulting in extremely decreased AMH production, leading to PMDS in this patient. This is the first description of an AMH promoter mutation leading to PMDS.