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/&#x394; for simplicity. A subset of female heterozygotes (Eif4enif1WT/&#x394;) had no litters. In those with litters, the final litter was earlier (5.4 &#xb1; 2.6 vs 10.5 &#xb1; 0.7 months; P = .02). Heterozygous breeding pair (Eif4enif1WT/&#x394; &#xd7; Eif4enif1WT/&#x394;) litter size was 60% of WT litter size (3.9 &#xb1; 2.0 vs 6.5 &#xb1; 3.0 pups/litter; P < .001). The genotypes were 35% Eif4enif1WT/flx and 65% Eif4enif1WT/&#x394;, with no homozygotes. Homozygote embryos did not develop beyond the 4- to 8-cell stage. The number of follicles in ovaries from Eif4enif1WT/&#x394; mice was lower starting at the primordial (499 &#xb1; 290 vs 1445 &#xb1; 381) and primary follicle stage (1069 &#xb1; 346 vs 1450 &#xb1; 193) on day 10 (P < .05). The preantral follicle number was lower starting on day 21 (213 &#xb1; 86 vs 522 &#xb1; 227; P < .01). Examination of ribosome protected mRNAs demonstrated altered mRNA expression. The Eif4enif1 stop-gain mice replicate the POI phenotype in women based on an earlier end to reproduction due to oocyte loss. The unique mouse model provides a platform to study regulation of protein translation across oocyte and embryo development in mammals.