Identification of a new missense mutation (Gly95Glu) in a highly conservedcodon within the high-mobility group box of the sex-determining Region Y gene: Report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor

Leydig cells and Sertoli cells of the testes produce hormones that cause ma le differentiation, if receptors are present. The Y chromosomal SRY gene (s ex determining Region Y gene) acts as TDF and is required for regular male sex determination. SRY represents a transcription factor belonging to the s uperfamily of genes sharing the HMG-box motif (high-mobility group-box), wh ich acts as DNA binding region. Here, we describe a nonmosaic XY sex-revers ed female with pure gonadal dysgenesis (46,XY karyotype, completely female external genitalia, normal Mullerian ducts, absence of Wolffian ducts, stre ak gonads) who harbored a yolk-sac tumor and was referred for the assessmen t of primary amenorrhea. Using genomic PCR analysis, a 423-bp PCR product, encompassing the HMG-box of the SRY gene, was amplified from the proposita, her father, and her three brothers, whereas no band was visible in the pat ient's mother and her three sisters. The PCR products were sequenced for mu tations subsequently. A new de novo missense mutation within the HMG-box of the SRY gene was discovered in the proposita. A G is replaced by an A in c odon 95 at position +284, resulting in the replacement of the nonpolar amin oacid glycine by the polar amino acid glutamate. The glycine at codon 95 is highly conserved between the family of HMG-box proteins and between specie s. This point mutation has not been described earlier and brings the total number of SRY mutations described so far to 36, each mutation being unique. This mutation was not detected in the patient's father and her male siblin gs. The present data provide further evidence to support the functional imp ortance of the putative DNA binding activity of the SRY HMG-box domain.