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

Gershoni, Moran; Braun, Tslil; Hauser, Ron; Barda, Shimi; Lehavi, Ofer; Malcov, Mira; Frumkin, Tsvia; Kalma, Yael; Pietrokovski, Shmuel; Arama, Eli; Kleiman, Sandra E.

doi:10.1016/j.xhgg.2023.100189

Cited by 2 publications

(3 citation statements)

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“…Serving as the closest paralog to RNF212, RNF212B shares functional significance in controlling recombination rate in mammals [ 134 , 152 , 153 ]. In a recent whole-exome sequency study in patients with severe male infertility Gershoni et al [ 154 ] brought to light a pathogenic variant of the RNF212B gene causing a substitution at position 448 (C448T), that results in the conversion of the arginine-150 codon to a premature stop codon. This alteration predicts a truncation of the C-terminal half of the protein.…”

Section: Recombination-dependent Mechanism Of Chromosome Pairing and ...mentioning

confidence: 99%

“…This alteration predicts a truncation of the C-terminal half of the protein. The patients carrying the homozygous RNF212B C448T variant suffer of a severe chromosome nondisjunction defect in sperm cells, especially of the sex chromosomes [ 154 ]. This observation suggests that RNF212B has a functional role in the processing of DSBs formed in the PAR, although not strictly specific.…”

Section: Recombination-dependent Mechanism Of Chromosome Pairing and ...mentioning

confidence: 99%

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Recent advances in mechanisms ensuring the pairing, synapsis and segregation of XY chromosomes in mice and humans

Lampitto,

Barchi

2024

Cell. Mol. Life Sci.

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Sex chromosome aneuploidies are among the most common variations in human whole chromosome copy numbers, with an estimated prevalence in the general population of 1:400 to 1:1400 live births. Unlike whole-chromosome aneuploidies of autosomes, those of sex chromosomes, such as the 47, XXY aneuploidy that causes Klinefelter Syndrome (KS), often originate from the paternal side, caused by a lack of crossover (CO) formation between the X and Y chromosomes. COs must form between all chromosome pairs to pass meiotic checkpoints and are the product of meiotic recombination that occurs between homologous sequences of parental chromosomes. Recombination between male sex chromosomes is more challenging compared to both autosomes and sex chromosomes in females, as it is restricted within a short region of homology between X and Y, called the pseudo-autosomal region (PAR). However, in normal individuals, CO formation occurs in PAR with a higher frequency than in any other region, indicating the presence of mechanisms that promote the initiation and processing of recombination in each meiotic division. In recent years, research has made great strides in identifying genes and mechanisms that facilitate CO formation in the PAR. Here, we outline the most recent and relevant findings in this field. XY chromosome aneuploidy in humans has broad-reaching effects, contributing significantly also to Turner syndrome, spontaneous abortions, oligospermia, and even infertility. Thus, in the years to come, the identification of genes and mechanisms beyond XY aneuploidy is expected to have an impact on the genetic counseling of a wide number of families and adults affected by these disorders.

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Section: Recombination-dependent Mechanism Of Chromosome Pairing and ...mentioning

confidence: 99%

Section: Recombination-dependent Mechanism Of Chromosome Pairing and ...mentioning

confidence: 99%

Recent advances in mechanisms ensuring the pairing, synapsis and segregation of XY chromosomes in mice and humans

Lampitto,

Barchi

2024

Cell. Mol. Life Sci.

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“…Here we characterize RNF212B, a third mammalian Zip3-family member. Alleles of Rnf212b have been linked to heritable variation in crossover rate in cattle, Soay sheep, and red deer 38-41 ; and a rare human RNF212B variant was recently associated with male infertility 42 . We show that mouse RNF212B undergoes crossover-specific patterning along SCs and is essential for crossing over and fertility in males and females.…”

Section: Introductionmentioning

confidence: 99%

Distinct and interdependent functions of three RING proteins regulate recombination during mammalian meiosis

Ito,

Yun,

Kulkarni

et al. 2023

Preprint

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SUMMARYCrossing-over between homologous chromosomes is essential for accurate segregation during meiosis. In mammals, factors required for crossing over include RNF212 and HEI10, RING-finger domain proteins implicated in modification by SUMO and ubiquitin, respectively. Here we show that a third RING protein, RNF212B, is essential for crossing over in mouse and characterize its relationships with RNF212 and HEI10. Mutant analysis indicates that, analogous to RNF212, RNF212B regulates recombination occurring in the context of synapsed chromosomes by stabilizing pro-crossover factors, regulating the progression of recombination, and enabling the differentiation and maturation of crossover-specific recombination complexes. Also, like RNF212, RNF212B localizes between synapsed chromosomes, initially as numerous foci along synaptonemal complexes (SCs) before undergoing HEI10-dependent redistribution to accumulate at prospective crossover sites. Despite these similarities, accumulation of RNF212B at nascent crossover sites is much greater than RNF212 and occurs earlier, coincident with the appearance of HEI10 foci, implicating concerted action of RNF212B and HEI10 in the differentiation of crossover sites. RNF212B localization also shows greater dependence on DNA double-strand breaks and SC formation than RNF212. Together, our analysis delineates three distinct but interdependent RING proteins that regulate meiotic recombination by integrating signals from DSBs, synapsis, the cell-cycle, and developing crossover sites.

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

Cited by 2 publications

References 80 publications

Recent advances in mechanisms ensuring the pairing, synapsis and segregation of XY chromosomes in mice and humans

Recent advances in mechanisms ensuring the pairing, synapsis and segregation of XY chromosomes in mice and humans

Distinct and interdependent functions of three RING proteins regulate recombination during mammalian meiosis

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