An ENU-induced mutation in the mouse Rnf212 gene is associated with male meiotic failure and infertility

Abstract

The ENU-induced repro57 mutation was identified in an unbiased screen for the discovery of novel genes for fertility. Male repro57 homozygous mice are infertile, and exhibit significantly reduced testis weight compared to wild type. Histological examination of mutant testes revealed that spermatocytes degenerated during late prophase, and no mature spermatozoa were found in the seminiferous epithelium, suggesting that infertility is caused by arrest of spermatogenesis at late meiotic prophase. Consistent with this hypothesis, the number of foci with MLH1, a protein essential for crossing over, is greatly reduced in repro57 mutant spermatocytes, which also lack chiasmata between homologs and exhibit premature dissociation of XY chromosomes. In repro57 mutant mice, we identified a mutation in the Rnf212 gene, encoding Ring Finger Protein 212. The overall phenotype of repro57 mouse is consistent with the recently reported phenotype of the Rnf212 knockout mouse; slight differences may be due to genetic background effects. Thus, the repro57 nonsense mutation provides a new allele of the mouse Rnf212 gene.

A pathogenic variant in the uncharacterized RNF212B gene results in severe aneuploidy male infertility and repeated IVF failure

“…Nevertheless, although we cannot rule out the possibility of some post-meiotic impairments, we attribute the etiology for infertility in P-1 and P-2 mainly to the severe genome instability detected in sperm and embryos derived from these patients, which is consistent with a role of this family of proteins in the homologous recombination-related processes during meiosis I. 42 , 44 Likewise, the Drosophila Zip3/RNF212 -related genes may also function either during the pairing of the homologous chromosomes or at post-meiotic stages. Since an early role in homolog pairing or a late post-meiotic role has never been demonstrated for this family of proteins, identifying their exact role in Drosophila spermatogenesis shall shed light on a new or more refined function of these proteins during the homologous recombination stage, which could be then tested in higher model organisms.…”

“…In accordance with the expression data, orthologous genes in both flies and mammals were reported to affect meiotic recombination rate, pairing of the homologous chromosomes, and/or crossover maturation. 38 , 39 , 40 , 41 , 42 , 43 Furthermore, a previous study demonstrated dosage-dependent aneuploidy in Rnf212 knockout mice. 44 To more directly explore a possible role of RNF212B in meiotic recombination, we set out to examine the chromosomal ploidy status of sperm cells and embryos derived from our patients carrying the RNF212B C448T variant.…”

Hybrid Sterility with Meiotic Metaphase Arrest in Intersubspecific Mouse Crosses

“…As part of recent forward genetic studies for linkage mapping, we generated F 1 /F 2 hybrid mice from matings between domesticusderived laboratory strains and the JF1/MsJ (JF1 mol ) strain, which was derived from the Mus musculus molossinus (hereafter molossinus) subspecies (Asano et al 2009;Khalaj et al 2014;Fujiwara et al 2015). We observed that the F 1 and F 2 hybrid males thus frequently produced spermatogenic abnormalities.…”

R-Loop Formation in Meiosis: Roles in Meiotic Transcription-Associated DNA Damage

“…Some meiotic genes, including Spo11 and Rnf212 , function in a dose-dependent manner [ 110 , 111 , 112 , 113 ]. Therefore, the precise regulation of transcription is essential during early prophase, especially at the onset of meiosis, by both STRA8/MEIOSIN-dependent regulation [ 30 , 31 ] and STRA8-independent regulation.…”