TAC3 and TACR3 Mutations in Familial Hypogonadotropic Hypogonadism Reveal a Key Role for Neurokinin B in the Central Control of Reproduction

Overview

Journal Nat Genet

Specialty Genetics

Date 2008 Dec 17

PMID 19079066

Citations 347

Authors

A Kemal Topaloglu

Frank Reimann

Metin Guclu

Ayse Serap Yalin

L Damla Kotan

Keith M Porter

Ayse Serin

Neslihan O Mungan

Joshua R Cook

Sazi Imamoglu

N Sema Akalin

Bilgin Yuksel

Stephen ORahilly

Robert K Semple

Affiliations

Soon will be listed here.

Abstract

The timely secretion of gonadal sex steroids is essential for the initiation of puberty, the postpubertal maintenance of secondary sexual characteristics and the normal perinatal development of male external genitalia. Normal gonadal steroid production requires the actions of the pituitary-derived gonadotropins, luteinizing hormone and follicle-stimulating hormone. We report four human pedigrees with severe congenital gonadotropin deficiency and pubertal failure in which all affected individuals are homozygous for loss-of-function mutations in TAC3 (encoding Neurokinin B) or its receptor TACR3 (encoding NK3R). Neurokinin B, a member of the substance P-related tachykinin family, is known to be highly expressed in hypothalamic neurons that also express kisspeptin, a recently identified regulator of gonadotropin-releasing hormone secretion. These findings implicate Neurokinin B as a critical central regulator of human gonadal function and suggest new approaches to the pharmacological control of human reproduction and sex hormone-related diseases.

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