New IHH Gene

[Guest guest]

Looks like the Boston group found a new gene. This just out from the

New England Journal of Medicine:

The GPR54 Gene as a Regulator of Puberty

B. Seminara, M.D., Sophie Messager, Ph.D., Emmanouella E.

Chatzidaki, B.Sc., Rosemary R. Thresher, Ph.D., S. Acierno, Jr.,

B.S., Jenna K. Shagoury, B.S., Yousef Bo-Abbas, M.D., Kuohung,

M.D., e M. Schwinof, M.A., Alan G. Hendrick, Ph.D., Dirk Zahn,

Ph.D., Dixon, B.A., Ursula B. Kaiser, M.D., A.

Slaugenhaupt, Ph.D., F. Gusella, Ph.D., O'Rahilly, M.D.,

Mark B.L. Carlton, Ph.D., F. Crowley, Jr., M.D., A.J.R.

Aparicio, B.M., B.Ch., Ph.D., and H. Colledge, Ph.D.

ABSTRACT

Background Puberty, a complex biologic process involving sexual

development, accelerated linear growth, and adrenal maturation, is

initiated when gonadotropin-releasing hormone begins to be secreted by

the hypothalamus. We conducted studies in humans and mice to identify

the genetic factors that determine the onset of puberty.

Methods We used complementary genetic approaches in humans and in

mice. A consanguineous family with members who lacked pubertal

development (idiopathic hypogonadotropic hypogonadism) was examined

for mutations in a candidate gene, GPR54, which encodes a G

protein?coupled receptor. Functional differences between wild-type and

mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient

mouse model was created and phenotyped. Responsiveness to exogenous

gonadotropin-releasing hormone was assessed in both the humans and the

mice.

Results Affected patients in the index pedigree were homozygous for an

L148S mutation in GPR54, and an unrelated proband with idiopathic

hypogonadotropic hypogonadism was determined to have two separate

mutations, R331X and X399R. The in vitro transfection of COS-7 cells

with mutant constructs demonstrated a significantly decreased

accumulation of inositol phosphate. The patient carrying the compound

heterozygous mutations (R331X and X399R) had attenuated secretion of

endogenous gonadotropin-releasing hormone and a left-shifted

dose?response curve for gonadotropin-releasing hormone as compared

with six patients who had idiopathic hypogonadotropic hypogonadism

without GPR54 mutations. The Gpr54?deficient mice had isolated

hypogonadotropic hypogonadism (small testes in male mice and a delay

in vaginal opening and an absence of follicular maturation in female

mice), but they showed responsiveness to both exogenous gonadotropins

and gonadotropin-releasing hormone and had normal levels of

gonadotropin-releasing hormone in the hypothalamus.

Conclusions Mutations in GPR54, a G protein?coupled receptor gene,

cause autosomal recessive idiopathic hypogonadotropic hypogonadism in

humans and mice, suggesting that this receptor is essential for normal

gonadotropin-releasing hormone physiology and for puberty.

Source Information

From the Reproductive Endocrine Unit (S.B.S., J.S.A., J.K.S., K.M.S.,

W.F.C.) and the Molecular Neurogenetics Unit, Center for Human Genetic

Research (S.A.S., J.F.G.), Massachusetts General Hospital; the

Division of Endocrinology, Diabetes, and Hypertension, Department of

Medicine, Brigham and Women's Hospital and Harvard Medical School

(W.K., U.B.K.); and the Harvard Institute of Human Genetics, Harvard

Medical School (S.A.S., J.F.G.) ? all in Boston; Paradigm Therapeutics

(S.M., R.R.T., A.G.H., D.Z., J.D., M.B.L.C., S.A.J.R.A, W.H.C.); the

Departments of Physiology (E.E.C., W.H.C.), Oncology (S.A.J.R.A.), and

Clinical Biochemistry (S.O.) and the Cambridge Institute for Medical

Research, Addenbrooke's Hospital (S.O.), University of Cambridge,

Cambridge, United Kingdom; and the Faculty of Medicine, Kuwait

University, Al-Jabriyah (Y.B.-A.).