Journal Article

An ancient founder mutation in <i>PROKR2</i> impairs human reproduction

Magdalena Avbelj Stefanija, Marc Jeanpierre, Gerasimos P. Sykiotis, Jacques Young, Richard Quinton, Ana Paula Abreu, Lacey Plummer, Margaret G. Au, Ravikumar Balasubramanian, Andrew A. Dwyer, Jose C. Florez, Timothy Cheetham, Simon H. Pearce, Radhika Purushothaman, Albert Schinzel, Michel Pugeat, Elka E. Jacobson-Dickman, Svetlana Ten, Ana Claudia Latronico, James F. Gusella, Catherine Dode, William F. Crowley and Nelly Pitteloud

in Human Molecular Genetics

Volume 21, issue 19, pages 4314-4324
Published in print October 2012 | ISSN: 0964-6906
Published online July 2012 | e-ISSN: 1460-2083 | DOI:
An ancient founder mutation in PROKR2 impairs human reproduction

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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 mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ∼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.

Journal Article.  5848 words.  Illustrated.

Subjects: Genetics and Genomics

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