Hypogonadotropic hypogonadism in an adult female with a heterozygous hypomorphic mutation of SOX2.

OBJECTIVE Heterozygous SOX2 mutations have recently been reported to cause isolated hypogonadotropic hypogonadism (HH), in addition to ocular and brain abnormalities. Here, we report a further case with a heterozygous hypomorphic SOX2 mutation and isolated HH. PATIENT The patient was a 28-year-old Japanese female with congenital right anophthalmia and poor pubertal development, who was found to have HH by a gonadotropin-releasing hormone test (peak serum LH, 2.3 mIU/ml; peak serum FSH, 2.9 mIU/ml). Other pituitary hormones were normal. METHODS We performed mutation analysis of SOX2 and functional studies of mutant SOX2 protein using the core enhancer sequence of the chicken delta-1-crystallin gene (DC5) and that of the mouse nestin gene (Nes30). RESULTS A heterozygous missense mutation (224T > A, Leu75Gln) was identified in the DNA-binding domain. The mutant SOX2 protein had a severely reduced (approximately 10%) DNA-binding affinity and a markedly diminished (20-30%) transactivation potential with no dominant negative effect. CONCLUSIONS The results provide further support for the positive role of SOX2 in the regulation of gonadotropin production.