Document Detail

Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.
MedLine Citation:
PMID:  17959774     Owner:  NLM     Status:  MEDLINE    
Gonadotropin-releasing hormone (GnRH) deficiency in the human presents either as normosmic idiopathic hypogonadotropic hypogonadism (nIHH) or with anosmia [Kallmann syndrome (KS)]. To date, several loci have been identified to cause these disorders, but only 30% of cases exhibit mutations in known genes. Recently, murine studies have demonstrated a critical role of the prokineticin pathway in olfactory bulb morphogenesis and GnRH secretion. Therefore, we hypothesize that mutations in prokineticin 2 (PROK2) underlie some cases of KS in humans and that animals deficient in Prok2 would be hypogonadotropic. One hundred IHH probands (50 nIHH and 50 KS) with no known mutations were examined for mutations in the PROK2 gene. Mutant PROK2s were examined in functional studies, and the reproductive phenotype of the Prok2(-/-) mice was also investigated. Two brothers with KS and their sister with nIHH harbored a homozygous deletion in the PROK2 gene (p.[I55fsX1]+[I55fsX1]). Another asymptomatic brother was heterozygous for the deletion, whereas both parents (deceased) had normal reproductive histories. The identified deletion results in a truncated PROK2 protein of 27 amino acids (rather than 81 in its mature form) that lacks bioactivity. In addition, Prok2(-/-) mice with olfactory bulb defects exhibited disrupted GnRH neuron migration, resulting in a dramatic decrease in GnRH neuron population in the hypothalamus as well as hypogonadotropic hypogonadism. Homozygous loss-of-function PROK2 mutations cause both KS and nIHH.
Nelly Pitteloud; Chengkang Zhang; Duarte Pignatelli; Jia-Da Li; Taneli Raivio; Lindsay W Cole; Lacey Plummer; Elka E Jacobson-Dickman; Pamela L Mellon; Qun-Yong Zhou; William F Crowley
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-10-24
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  104     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-11-05     Completed Date:  2007-12-27     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17447-52     Citation Subset:  IM    
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MeSH Terms
Base Sequence
Cell Movement
Gastrointestinal Hormones / deficiency,  genetics,  metabolism*
Gene Deletion
Gene Expression Regulation
Gonadotropin-Releasing Hormone / metabolism
Hypogonadism / genetics,  metabolism*,  pathology*
Kallmann Syndrome / genetics,  metabolism*,  pathology*
Mice, Knockout
Mutation / genetics
Neurons / cytology,  metabolism
Neuropeptides / deficiency,  genetics,  metabolism*
Grant Support
5R01 HD015788/HD/NICHD NIH HHS; DK044838/DK/NIDDK NIH HHS; HD020377/HD/NICHD NIH HHS; MH067753/MH/NIMH NIH HHS; R01 DK044838/DK/NIDDK NIH HHS; R01 DK044838-18/DK/NIDDK NIH HHS; R01 DK044838-19/DK/NIDDK NIH HHS; R01 HD015788/HD/NICHD NIH HHS; U54 HD012303/HD/NICHD NIH HHS; U54 HD012303/HD/NICHD NIH HHS; U54 HD012303-27/HD/NICHD NIH HHS; U54 HD012303-270011/HD/NICHD NIH HHS; U54 HD012303-28/HD/NICHD NIH HHS; U54 HD012303-280011/HD/NICHD NIH HHS; U54 HD028138/HD/NICHD NIH HHS; U54 HD028138/HD/NICHD NIH HHS; U54 HD029164/HD/NICHD NIH HHS
Reg. No./Substance:
0/Gastrointestinal Hormones; 0/Neuropeptides; 0/PROK2 protein, human; 0/Prok2 protein, mouse; 33515-09-2/Gonadotropin-Releasing Hormone

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