Novel C617Y mutation in the 7th transmembrane segment of luteinizing hormone/choriogonadotropin receptor in a Japanese boy with peripheral precocious puberty.
Testotoxicosis, also known as familial male-limited precocious puberty, is an autosomal dominant form of gonadotropin-independent precocious puberty caused by heterozygous constitutively activating mutations of the LHCGR gene encoding the luteinizing hormone/choriogonadotropin receptor (LH/CGR). The patient is an 8-year-old boy who started to develop pubic hair and penile enlargement at 6 years of age. The patient had elevated serum testosterone levels, but initially exhibited a prepubertal response of gonadotropins to GnRH, which was followed by central activation of the hypothalamo-pituitary-gonadal axis. The father reported having experienced precocious puberty, and is 158 cm tall. There is no history of short stature and precocious puberty in the family except for the father. The LHCGR gene was analyzed by direct DNA sequencing of amplified PCR products from the patient and his parents. The wild-type and mutant LH/CGRs were transiently expressed in COS-1 cells and cAMP levels in the cells were determined with or without hCG stimulation. Genetic analysis revealed a novel C617Y mutation of the LHCGR gene in the patient and his mother, while his father had no mutations. Functional expression study demonstrated around 15% increase in the basal intracellular cAMP level in cells expressing the mutant LH/CGR compared with that in cells expressing the wild-type receptor. We have reported the first missense C617Y mutation located in the 7th transmembrane segment of LH/CGR causing testotoxicosis. The modest phenotype of our patient may be explained, at least in part, by the modest increase in the intracellular cAMP level caused by the C617Y mutation.
Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. nagasaki@med.niigata-u.ac.jp
Keisuke
K
Nagasaki
Noriyuki
N
Katsumata
Yohei
Y
Ogawa
Toru
T
Kikuchi
Makoto
M
Uchiyama
D000818:Animals; D001827:Body Height; D001835:Body Weight; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis; D015870:Gene Expression; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D007564:Japan; D008297:Male; D017258:Medroxyprogesterone Acetate / Q000627:therapeutic use; D020125:Mutation, Missense / Q000235:genetics*; D010413:Penis / Q000254:growth & development; D016133:Polymerase Chain Reaction; D011629:Puberty, Precocious / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D011974:Receptors, LH / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013255:Steroid 21-Hydroxylase / Q000235:genetics; D013737:Testis / Q000503:physiopathology; D013739:Testosterone / Q000097:blood
D006063:Chorionic Gonadotropin; D011974:Receptors, LH; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D017258:Medroxyprogesterone Acetate; D000242:Cyclic AMP; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase