NCBI Summary:
This gene encodes an ankyrin repeat protein that belongs to the death receptor-associated family of proteins and plays a role in mediating apoptosis. The encoded protein is also thought to function in the replication stress-induced checkpoint signaling pathway via interaction with checkpoint kinase 1. [provided by RefSeq, Aug 2013]
General function
Apoptosis
Comment
Cellular localization
Comment
candidate123
Ovarian function
Comment
Expression regulated by
Comment
Ovarian localization
Oocyte
Comment
FEM1 proteins are ancient regulators of SLBP degradation. Dankert JF et al. (2017) FEM1A, FEM1B, and FEM1C are evolutionarily-conserved VHL-box proteins, the substrate recognition subunits of CUL2-RING E3 ubiquitin ligase complexes. Here, we report that FEM1 proteins are ancient regulators of Stem-Loop Binding Protein (SLBP), a conserved protein that interacts with the stem loop structure located in the 3' end of canonical histone mRNAs and functions in mRNA cleavage, translation and degradation. SLBP levels are highest during S-phase coinciding with histone synthesis. The ubiquitin ligase complex SCF(cyclin F) targets SLBP for degradation in G2 phase; however, the regulation of SLBP during other stages of the cell cycle is poorly understood. We provide evidence that FEM1A, FEM1B, and FEM1C interact with and mediate the degradation of SLBP. Cyclin F, FEM1A, FEM1B and FEM1C all interact with a region in SLBP's N-terminus using distinct degrons. An SLBP mutant that is unable to interact with all four ligases is expressed at higher levels than wild type SLBP and does not oscillate during the cell cycle. We demonstrate that orthologues of SLBP and FEM1 proteins interact in C. elegans and D. melanogaster, suggesting that the pathway is evolutionarily conserved. Furthermore, we show that FEM1 depletion in C. elegans results in the upregulation of SLBP orthologue CDL-1 in oocytes. Notably, cyclin F is absent in flies and worms, suggesting that FEM1 proteins play an important role in SLBP targeting in lower eukaryotes.//////////////////
Follicle stages
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: FEM1A and FEM1B: novel candidate genes for polycystic ovary syndrome. Goodarzi MO et al. BACKGROUND Human homologs (FEM1A, FEM1B, FEM1C) of nematode sex determination genes are candidate genes for polycystic ovary syndrome (PCOS). We previously identified a FEM1A mutation (H500Y) in a woman with PCOS; FEM1B has been implicated in insulin secretion. METHODS Women with and without PCOS (287 cases, 187 controls) were genotyped for H500Y and six FEM1A single nucleotide polymorphisms (SNPs), five FEM1B SNPs and five FEM1C SNPs. SNPs and haplotypes were determined and tested for association with PCOS and component phenotypes. RESULTS No subject carried the FEM1A H500Y mutation. FEM1A SNPs rs8111933 (P = 0.001) and rs12460989 (P = 0.046) were associated with an increased likelihood of PCOS whereas FEM1A SNP rs1044386 was associated with a reduced probability of PCOS (P = 0.013). FEM1B SNP rs10152450 and a linked SNP were associated with a reduced likelihood of PCOS (P = 0.005), and lower homeostasis model assessment (HOMA) for beta-cell function (HOMA-%B, P = 0.011) and lower HOMA for insulin resistance (HOMA-IR, P = 0.018). FEM1B SNP rs12909277 was associated with lower HOMA-%B (P = 0.008) and lower HOMA-IR (P = 0.037). Haplotype associations were consistent with SNP results, and also revealed association of FEM1B haplotype TGAGG with increased HOMA-%B (P = 0.007) and HOMA-IR (P = 0.024). FEM1C variants were not associated with PCOS. CONCLUSIONS This study presents evidence suggesting a role for FEM1A and FEM1B in the pathogenesis of PCOS. Only FEM1B variants were associated with insulin-related traits in PCOS women, consistent with prior evidence linking this gene to insulin secretion. Replication of these associations and mechanistic studies will be necessary to establish the role of these genes in PCOS.