Incidental Mutation 'R0069:Ccnb1ip1'

• ID: 16904
• Institutional Source: Beutler Lab
• Gene Symbol: Ccnb1ip1
• Ensembl Gene: ENSMUSG00000071470
• Gene Name: cyclin B1 interacting protein 1
• Synonyms: mei4, Hei10, LOC239083
• MMRRC Submission: 038360-MU
• Essential gene?: Non essential (E-score: 0.000)
• Stock #: R0069 (G1)
• Status: Validated
• Chromosome: 14
• Chromosomal Location: 51026706-51033185 bp(-) (GRCm39)
• Type of Mutation: nonsense
• DNA Base Change (assembly): G to A at 81519382 bp (GRCm38)
• Zygosity: Heterozygous
• Amino Acid Change: Glutamine to Stop codon at position 322 (Q322*)
• Ref Sequence: ENSEMBL: ENSMUSP00000061341
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000057067]
• AlphaFold: D3Z3K2
• Predicted Effect: probably null; Transcript: ENSMUST00000057067; AA Change: Q322*
• SMART Domains: Protein: ENSMUSP00000061341; Gene: ENSMUSG00000043289; AA Change: Q322*

Domain	Start	End	E-Value	Type
Pfam:Mei4	1	378	9.3e-89	PFAM

• Meta Mutation Damage Score: 0.9755
• Coding Region Coverage:
  • 1x: 86.4%
  • 3x: 80.4%
  • 10x: 57.4%
  • 20x: 26.1%
• Validation Efficiency: 94% (60/64)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] HEI10 is a member of the E3 ubiquitin ligase family and functions in progression of the cell cycle through G(2)/M.[supplied by OMIM, Apr 2004] ; PHENOTYPE: Mice homozygous for an ENU-induced mutation have abnormal testicular and ovarian morphology and exhibit sterility in both sexes owing to meiotic defects. [provided by MGI curators]
• Allele List at MGI:

  All alleles(7) : Targeted(3) Gene trapped(3) Chemically induced(1)

• Posted On: 2013-01-20
• Science Writer: Anne Murray

Protein Function and Prediction

Ccnb1ip1 encodes HEI10, an E3 ubiquitin ligase that promotes the progression of the cell cycle through G2/M by reducing cyclin B levels (1-3). The HEI10 protein has a divergent RING finger motif at the N-terminus, a coiled-coil domain, and cyclin and cyclin-dependent kinase phosphorylation sites at the C-terminus (1). HEI10 is essential for chiasmata formation and fertility in mice (4). Yeast 2-hybrid screens revealed that HEI10 interacts with SUMO2 and other proteins with consensus sumoylation sites (4). This indicates that HEI10 functions as an E3 ligase in the sumoylation cascade (4). Strong et al. propose that HEI10 is a meiosis-specific SUMO E3 ligase that functions in the resolution of recombination intermediates into mature chiasmata (4). Ward et al. propose that HEI10 disrupts the association of CDK2 with CCNB3, subsequently allowing CDK2 to recruit MLH1 and MLH3 to designated crossover sites (5).

Expression/Localization

Northern blot analysis identified a 1.6-kb Ccnb1ip1 transcript at high levels in the heart, moderate levels in the kidney and liver, and low levels in the palcenta, brain and lung (1).

Background

Ccnb1ip1^mei4/mei4; MGI:3050548

involves: C3HeB/FeJ * C57BL/6J

Ccnb1ip1^mei4 bears a donor splice site mutation resulting in an aberrantly spliced transcript (5). Mice homozygous for an ENU-induced mutation have abnormal testicular and ovarian morphology and exhibit sterility in both sexes owing to meiotic defects (5;6).

References

  1. Toby, G. G., Gherraby, W., Coleman, T. R., and Golemis, E. A. (2003) A Novel RING Finger Protein, Human Enhancer of Invasion 10, Alters Mitotic Progression through Regulation of Cyclin B Levels. Mol Cell Biol. 23, 2109-2122.

  2. Singh, M. K., Nicolas, E., Gherraby, W., Dadke, D., Lessin, S., and Golemis, E. A. (2007) HEI10 Negatively Regulates Cell Invasion by Inhibiting Cyclin B/Cdk1 and Other Promotility Proteins. Oncogene. 26, 4825-4832.

  3. Gronholm, M., Muranen, T., Toby, G. G., Utermark, T., Hanemann, C. O., Golemis, E. A., and Carpen, O. (2006) A Functional Association between Merlin and HEI10, a Cell Cycle Regulator. Oncogene. 25, 4389-4398.

  4. Strong, E. R., and Schimenti, J. C. (2010) Evidence Implicating CCNB1IP1, a RING Domain-Containing Protein Required for Meiotic Crossing Over in Mice, as an E3 SUMO Ligase. Genes (Basel). 1, 440-451.

  5. Ward, J. O., Reinholdt, L. G., Motley, W. W., Niswander, L. M., Deacon, D. C., Griffin, L. B., Langlais, K. K., Backus, V. L., Schimenti, K. J., O'Brien, M. J., Eppig, J. J., and Schimenti, J. C. (2007) Mutation in Mouse hei10, an e3 Ubiquitin Ligase, Disrupts Meiotic Crossing Over. PLoS Genet. 3, e139.

  6. Ward, J. O., Reinholdt, L. G., Hartford, S. A., Wilson, L. A., Munroe, R. J., Schimenti, K. J., Libby, B. J., O'Brien, M., Pendola, J. K., Eppig, J., and Schimenti, J. C. (2003) Toward the Genetics of Mammalian Reproduction: Induction and Mapping of Gametogenesis Mutants in Mice. Biol Reprod. 69, 1615-1625.