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.
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 chickendelta-1-crystallin gene (DC5) and that of the mousenestin 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.
Authors: Qing Fang; Akima S George; Michelle L Brinkmeier; Amanda H Mortensen; Peter Gergics; Leonard Y M Cheung; Alexandre Z Daly; Adnan Ajmal; María Ines Pérez Millán; A Bilge Ozel; Jacob O Kitzman; Ryan E Mills; Jun Z Li; Sally A Camper Journal: Endocr Rev Date: 2016-11-09 Impact factor: 19.871
Authors: Michelle L Brinkmeier; Shannon W Davis; Piero Carninci; James W MacDonald; Jun Kawai; Debashis Ghosh; Yoshihide Hayashizaki; Robert H Lyons; Sally A Camper Journal: Genomics Date: 2009-02-11 Impact factor: 5.736
Authors: Sujatha A Jayakody; Cynthia L Andoniadou; Carles Gaston-Massuet; Massimo Signore; Anna Cariboni; Pierre M Bouloux; Paul Le Tissier; Larysa H Pevny; Mehul T Dattani; Juan P Martinez-Barbera Journal: J Clin Invest Date: 2012-09-04 Impact factor: 14.808
Authors: Daniel Kelberman; Sandra C P de Castro; Shuwen Huang; John A Crolla; Rodger Palmer; John W Gregory; David Taylor; Luciano Cavallo; Maria F Faienza; Rita Fischetto; John C Achermann; Juan Pedro Martinez-Barbera; Karine Rizzoti; Robin Lovell-Badge; Iain C A F Robinson; Dianne Gerrelli; Mehul T Dattani Journal: J Clin Endocrinol Metab Date: 2008-02-19 Impact factor: 5.958