Heterozygous Eif4nif1 Stop Gain Mice Replicate the Primary Ovarian Insufficiency Phenotype in Women

Abstract

We created the c.1286C>G stop-gain mutation found in a family with primary ovarian insufficiency (POI) at age 30 years. The Eif4enif1 C57/Bl6 transgenic mouse model contained a floxed exon 10-19 cassette with a conditional knock-in cassette containing the c.1286C>G stop-gain mutation in exon 10. The hybrid offspring of CMV-Cre mice with Eif4enif1WT/flx mice were designated Eif4enif1WT/{Delta} for simplicity. A subset of female heterozygotes (Eif4enif1WT/{Delta}) had no litters. In those with litters, the final litter was earlier (5.4{+/-}2.6 vs. 10.5{+/-}0.7 months; p=0.02). Heterozygous breeding pair (Eif4enif1WT/{Delta} x Eif4enif1WT/{Delta}) litter size was 60% of WT litter size (3.9{+/-}2.0 vs. 6.5{+/-}3.0 pups/litter; p<0.001). The genotypes were 35% Eif4enif1WT/flx and 65% Eif4enif1WT/{Delta}, with no homozygotes. Homozygote embryos did not develop beyond the 4-8 cell stage. The number of follicles in ovaries from Eif4enif1WT/{Delta} mice was lower starting at the primordial (499{+/-}290 vs. 1445{+/-}381) and primary follicle stage (1069{+/-}346 vs. 1450{+/-}193) on day 10 (p<0.05). The preantral follicle number was lower starting on day 21 (213{+/-}86 vs. 522{+/-}227; p<0.01). Examination of ribosome protected mRNAs (RPR) demonstrated altered mRNA expression. The Eif4enif1 stop-gain mice replicate the POI phenotype in women. The unique mouse model provides a platform to study regulation of protein translation across oocyte and embryo development in mammals.