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An ancient founder mutation in PROKR2 impairs human reproduction

Lookup NU author(s): Dr Richard Quinton, Dr Ravikumar Balasubramanian, Professor Timothy Cheetham, Professor Simon PearceORCiD


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Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutations age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same approximate to 123 kb haplotype whose population frequency is 10. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.

Publication metadata

Author(s): Stefanija MA, Jeanpierre M, Sykiotis GP, Young J, Quinton R, Abreu AP, Plummer L, Au MG, Balasubramanian R, Dwyer AA, Florez JC, Cheetham T, Pearce SH, Purushothaman R, Schinzel A, Pugeat M, Jacobson-Dickman EE, Ten S, Latronico AC, Gusella JF, Dode C, Crowley WF, Pitteloud N

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2012

Volume: 21

Issue: 19

Pages: 4314-4324

Print publication date: 05/07/2012

Date deposited: 13/08/2014

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/dds264


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Funder referenceFunder name
ANR-09-GENO-017Agence Nationale de la Recherche
P01 GM061354National Institutes of Health
R01 HD015788National Institutes of Health
R01 HD056264National Institutes of Health
P3-0343Slovene National Research Agency
U54 HD028138National Institutes of Health