TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction.
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.
Topaloglu
A Kemal
AK
Cukurova University, Faculty of Medicine, Department of Pediatric Endocrinology and Metabolism, Balcali, Adana, TURKEY.
Reimann
Frank
F
Cambridge Institute for Medical Research and Department of Clinical Biochemistry, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
Guclu
Metin
M
Uludag University, Faculty of Medicine, Department of Endocrinology and Metabolism, Bursa, TURKEY.
Yalin
Ayse Serap
AS
Marmara University, Faculty of Medicine, Department of Endocrinology and Metabolism, Istanbul, TURKEY.
Kotan
L Damla
LD
Cukurova University, Faculty of Medicine, Department of Forensic Medicine, Balcali, Adana, TURKEY.
Porter
Keith M
KM
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
Serin
Ayse
A
Cukurova University, Faculty of Medicine, Department of Forensic Medicine, Balcali, Adana, TURKEY.
Mungan
Neslihan O
NO
Cukurova University, Faculty of Medicine, Department of Pediatric Endocrinology and Metabolism, Balcali, Adana, TURKEY.
Cook
Joshua R
JR
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
Imamoglu
Sazi
S
Uludag University, Faculty of Medicine, Department of Endocrinology and Metabolism, Bursa, TURKEY.
Akalin
N Sema
NS
Marmara University, Faculty of Medicine, Department of Endocrinology and Metabolism, Istanbul, TURKEY.
Yuksel
Bilgin
B
Cukurova University, Faculty of Medicine, Department of Pediatric Endocrinology and Metabolism, Balcali, Adana, TURKEY.
O'Rahilly
Stephen
S
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
Semple
Robert K
RK
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
D000595:Amino Acid Sequence; D002894:Chromosomes, Human, Pair 4; D004252:DNA Mutational Analysis; D005190:Family; D006066:Gonads / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D059648:Kisspeptins; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D015287:Neurokinin B / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010375:Pedigree; D018042:Receptors, Neurokinin-3 / Q000235:genetics* / Q000378:metabolism; D012098:Reproduction / Q000235:genetics* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C106628:KISS1 protein, human; D059648:Kisspeptins; D018042:Receptors, Neurokinin-3; D025521:Tumor Suppressor Proteins; D015287:Neurokinin B