title: An ancient founder mutation in PROKR2 impairs human reproduction.
abstract: 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.
authors: Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston 02114, MA, USA.
authors: Magdalena
authors: M
authors: Avbelj Stefanija
authors: Marc
authors: M
authors: Jeanpierre
authors: Gerasimos P
authors: GP
authors: Sykiotis
authors: Jacques
authors: J
authors: Young
authors: Richard
authors: R
authors: Quinton
authors: Ana Paula
authors: AP
authors: Abreu
authors: Lacey
authors: L
authors: Plummer
authors: Margaret G
authors: MG
authors: Au
authors: Ravikumar
authors: R
authors: Balasubramanian
authors: Andrew A
authors: AA
authors: Dwyer
authors: Jose C
authors: JC
authors: Florez
authors: Timothy
authors: T
authors: Cheetham
authors: Simon H
authors: SH
authors: Pearce
authors: Radhika
authors: R
authors: Purushothaman
authors: Albert
authors: A
authors: Schinzel
authors: Michel
authors: M
authors: Pugeat
authors: Elka E
authors: EE
authors: Jacobson-Dickman
authors: Svetlana
authors: S
authors: Ten
authors: Ana Claudia
authors: AC
authors: Latronico
authors: James F
authors: JF
authors: Gusella
authors: Catherine
authors: C
authors: Dode
authors: William F
authors: WF
authors: Crowley
authors: Nelly
authors: N
authors: Pitteloud
mesh_terms: D019143:Evolution, Molecular; D005260:Female; D018703:Founder Effect; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency; D006239:Haplotypes; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism; D012098:Reproduction
chemical_list: C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D007987:Gonadotropin-Releasing Hormone