Two Ancient Mutations in the GNRHR Gene Expand the Founder Allelic Spectrum in Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 524-553-Male Reproductive Endocrinology
Bench to Bedside
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-550
Jin-Ho Choi*1, Ravikumar Balasubramanian1, Lacey C Plummer1, Cassandra L Buck1, Yunling Shi1, Marie-Laure Kottler2, Slawomir Wolczynski3, Ana Claudia Latronico4, Catherine Dode5, Tsutomu Ogata6, Lawrence C Layman7, James F Gusella8 and William F Crowley Jr.1
1Massachusetts General Hospital, Boston, MA, 2Ctre Hospitalier Univ, Caen, France, 3Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Bialystok, Poland, 4Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil., 5Institut Cochin, Paris, France, 6Hamamatsu University School of Medicine, Hamamatsu, Japan, 7Georgia Regents University, Augusta, GA, 8Massachusetts General Hospital, MA
Background: The ability to suppress reproduction may confer an adaptive evolutionary advantage to species during periods of stress, malnutrition and prolonged migration and hence be selected by genetic pressure over time. Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) represents a rare genetic disorder characterized by failure of reproductive function predominantly due to loss of function mutations. We recently reported a deleterious loss of function (LOF) founder mutation (p.L173R) in the PROKR2 gene in multiple IGD patients (1) across the world and also found it patients with hypothalamic amenorrhea, a functional IGD phenotype (2). This allele arose ~9,000 years ago and antedates the time of estimated accelerated human population growth that occurred ~5,000 years ago, suggesting a potential heterozygote advantage to allele carriers. We hypothesized that similar LOF founder alleles conferring such a heterozygote advantage to allele carriers may also exist in other IGD-associated genes.

Patients and methods: Reviewing our cohort of 1,371 patients with IGD and 328 probands from identified from the published literature, 12 recurrent (i.e. occurring in ≥3 different families) mutations in 6 genes known to cause IGD (GNRHR, TACR3, PROKR2, FGFR1, KAL1, and HS6ST1) surfaced as candidates for founder genes. Using single nucleotide polymorphisms (SNPs) and microsatellite markers encompassing >3X recombination hotspots on either side of the mutation, we defined the haplotype of each and estimated their age according to haplotype size and haplotype decay model.

Results: Two mutations in GNRHR, p.R262Q and p.R139H, were found to share a common ancestral haplotype in Caucasian IGD patients. The estimated age of p.R262Q and p.R139H alleles was ~4,700 and 4,800 years, respectively.

Conclusions: GNRHR p.R262Q and p.R139H mutations are new founder mutations and join an expanding list of founder alleles associated with IGD. In contrast to the PROKR2 founder allele, both GNRHR mutations arose after the onset of human population expansion suggesting a weak purifying selection of these alleles without a heterozygote advantage to carriers. The precise heterozygote advantage of the PROKR2 founder mutation requires further investigation.

(1) Avbelj Stefanija M, Jeanpierre M, Sykiotis GP, et al. An ancient founder mutation in PROKR2 impairs human reproduction. Hum Mol Genet 2012;21:4314-4324 (2) Caronia LM, Martin C, Welt CK, et al. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 2011;364:215-225.

Nothing to Disclose: JHC, RB, LCP, CLB, YS, MLK, SW, ACL, CD, TO, LCL, JFG, WFC Jr.

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm