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.

Figure 1.

Haplotypes of informative probands. For each STR marker, the number of dinucleotide repeats is shown. n.i. (not informative): alleles that cannot be unambiguously attributed to the L173R haplotype. Gray rectangle: region genotyped via SNP array analysis. Pink horizontal lines: haplotypes. Blue horizontal lines: haplotype regions identical to each other. In each of the homozygous probands (#2 and #12), the two haplotypes are labeled ‘a’ and ‘b’. The haplotype shared by all probands is marked with vertical dotted lines and is delimited by two major recombination hot spots on chromosome 20 (genomic region: NCBI build 36.1; recombination rates: HapMap, CEU population, public release #27).

Figure 2.

Haplotypes in the HA pedigree. Red arrow: proband. Haplotypes in the HA pedigree are shown with representative polymorphisms and the PROKR2 L173R mutation (c.518T>G). The mutation-bearing L173R haplotype is boxed red. SNPs and the mutation are stated according to the cDNA sequence, which is reverse and complementary to the genomic sequence.

Figure 3.

Informative previously unpublished pedigrees. Red circles: probands. Red numbers: probands' IDs. Haplotypes in Pedigree #3 are presented with representative polymorphisms and the PROKR2 L173R mutation (c.518T>G). The mutation-bearing L173R haplotype is boxed red. Black arrows indicate two siblings that have the same paternal and maternal PROKR2 haplotypes, yet are discordant for the disease. SNPs and the mutation are stated according to the cDNA sequence, which is reverse and complementary to the genomic.