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|Coordinate||71,027,954 bp (GRCm38)|
|Base Change||G ⇒ A (forward strand)|
|Gene Name||bicaudal C homolog 1 (Drosophila)|
|Chromosomal Location||70,922,832-71,159,700 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes an RNA-binding protein that is active in regulating gene expression by modulating protein translation during embryonic development. Mouse studies identified the corresponding protein to be under strict control during cell differentiation and to be a maternally provided gene product. [provided by RefSeq, Apr 2009]
PHENOTYPE: Homozygous inactivation of this gene causes heteroxia, impaired nodal flow, ventricular septal defects, partial prenatal lethality and postnatal death due to renal failure. Chemically induced mutants develop kidney cysts and may show bulging abdomens, bile duct anomalies and cardiovascular defects. [provided by MGI curators]
|Amino Acid Change||Threonine changed to Isoleucine|
|Institutional Source||Beutler Lab|
T86I in Ensembl: ENSMUSP00000014473 (fasta)
T86I in Ensembl: ENSMUSP00000123201 (fasta)
|Gene Model||not available|
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.999 (Sensitivity: 0.14; Specificity: 0.99)
|Phenotypic Category||Autosomal Recessive|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Embryos, Sperm, gDNA|
|Last Updated||2016-05-13 3:09 PM by Stephen Lyon|
The artemis phenotype was identified among ENU-mutagenized G3 mice when several animals from one pedigree were unexpectedly found dead. Upon analysis, the mice were found to have drastically enlarged kidneys. The phenotype segregated in a recessive Mendelian inheritance pattern, and was designated artemis. Artemis mice have enlarged polycystic kidneys, observable by 1 week of age. Urea levels are increased 5-fold in blood from artemis mice.
Homozygote artemis mice are viable but infertile. Heterozygotes are viable and fertile.
|Nature of Mutation|
The artemis mutation mapped to Chromosome 10, and corresponds to a C to T transition at position 275 of the Bicc1 transcript, in exon 3 of 21 total exons.
The mutated nucleotide is indicated in red lettering, and causes a threonine to isoleucine substitution at residue 86 of the Bicc1 protein.
The artemis mutation results in a threonine to isoleucine at position 86 of Bicc1, which resides in the N-terminal KH domain. This mutation is predicted to disrupt Bicc1 RNA-binding ability and/or destabilize the protein. Protein expression levels have not been examined in artemis tissue.
Bicc1mRNA is detected in mouse embryos as soon as they have implanted, and is observed at embryonic day 13 around sites of cartilage formation, in the presumptive diaphragm, pericardium, in the mesenchyme of the developing lung, and in the mesonephros and metanephros of the developing kidney (2). Total levels of Bicc1 mRNA in whole embryos increase slightly as embryogenesis proceeds (1). In the adult mouse, Bicc1 transcripts are found at high levels in the heart and kidney, with lower levels expressed in the testis (1;2). Bicc1 mRNA can also be detected in the stroma of primary oocytes, suggesting a maternal Bicc1 contribution exists in the mouse (2), in agreement with the finding that Drosophila Bicaudal-C is a maternal effect gene (3).
In mouse inner medullary collecting duct cells, Bicc1 displays a diffuse cytoplasmic localization (4).
bicaudal(bic) was first identified as a genetic factor affecting the anterior-posterior polarity of Drosophila embryos (5). The progeny of homozygous bic mutant female flies sometimes develop without structures from the anterior end of the embryo or with a double-abdomen, with two posterior ends arranged in mirror-image symmetry (3;5). Thus, bicaudal is a maternal effect gene with an incompletely penetrant phenotype. Subsequent genetic screening identified several new distinct loci causing similar defects in anterior-posterior patterning, one of which encoded the dominant maternal-effect mutation, Bicaudal-C (Bic-c) (3).
Mislocalization of pattern-determining RNAs, such as oskar (osk) and nanos (nos), during embryogenesis results in bicaudal embryos with posterior structures duplicated at their anterior ends (6;7). In progeny of Bic-C mutant females, the posterior determinant osk is mislocalized at the anterior of the embryos, suggesting that Bic-C functions to localize specific posterior RNAs during oogenesis (8). This is supported by data indicating that Bic-C protein (BIC-C) contains 5 KH domains (8) which allow it to bind RNA (9). Furthermore, at least one of its KH domains is required for its function, as a point mutation in the third KH domain causes a strong bicaudal phenotype (8). BIC-C also regulates osk translation (9).
The murine homologue of Bic-c (Bicc1 in mice) was identified by homology searches of cDNA sequences in GenBank (2), and later found to be the gene mutated to cause polycystic kidney disease in two mouse mutants (1). These two mouse strains have different mutant alleles of Bicc1, called jcpk and bpk. The jcpk allele was generated on a C57BL/6 background by random chlorambucil-induced mutagenesis (10;11), while the bpk allele arose spontaneously in the BALB/c strain (12). Homozygous jcpk mutants die before 10 days of age with numerous cysts in the kidneys, including in the proximal and distal tubules, collecting ducts and glomeruli (11). jcpk mutants display dilation of liver and pancreatic ducts. Approximately 30% of heterozygous jcpk mice also develop late-onset polycystic kidney disease affecting the glomeruli (11). In contrast, bpk mutants display a less severe phenotype distinct from that of jcpk mice, with polycystic kidneys that show dilation of the renal collecting ducts, and biliary dysgenesis (13;14). bpk mice live to approximately 4 weeks of age (13;14). Mouse embryos with a targeted deficiency of Bicc1 were reported to display randomized left-right asymmetry due to disruption of the planar alignment of motile cilia of the ventral node. Interestingly, polycystic kidney disease is also frequently linked to cilia defects, as for example in mice with mutations of Pkhd1 and inversin (15;16).
Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disease occurring in 1 in 20,000 humans (17), characterized by dilation of renal collecting ducts, biliary dysgenesis, and portal tract fibrosis (18). The PKHD1 gene has recently been identified as the principal causative disease gene (19). Before its identification, jcpk, bpk and several other mutants have been used as models to investigate the pathogenesis of ARPKD.
Primary apical cilia are present on epithelial cells of the nephron, biliary tract, and pancreatic ducts during adulthood (20). The association of polycystic kidney disease with deficiencies of cilium proteins including Pkhd1, inversin, and Tg737 (21;22) in mice suggests that dysfunction of cilia may underlie cyst formation. Although immortalized renal cells from Bicc1bpk mutants were reported to display normal ciliogenesis (23), their function was not examined.
Several reports suggest that mutations in Bicc1 cause polycystic kidneys by disrupting the normal polarity of renal epithelial cells. In cystic renal cells immortalized from the bpk mutant mouse, epidermal growth factor receptor (EGFR) was aberrantly localized to the apical cell membrane (Figure 2), in addition to its normal presence at the basolateral membrane (23). Abnormal EGFR sorting to the apical membrane has been observed in polycystic kidney disease caused by mutations in PKD1, PKD2, and PKHD1 (24;25). In addition, EGFR ligands have been detected in the apical medium of cultured cystic epithelial cells and in the cyst fluid of autosomal dominant polycystic kidney disease (ADPKD) patients (26). EGFR kinase inhibition improves kidney function in models of polycystic kidney disease (27).
In mouse inner medullary collecting duct cell lines in which Bicc1 was silenced by short hairpin RNA inhibition (shRNA), E-cadherin was mislocalized from cell-cell junctions to the cytoplasm (28). Impaired cell motility, tubulogenesis, and actin cytoskeletal organization were attributed to defective E-cadherin-dependent cell-cell adhesion in these cells. E-cadherin-mediated cell-cell adhesion triggers assembly of intercellular junctions, and is therefore essential for epithelial polarity and tubule formation.
The mechanism by which Bicc1 affects EGFR and E-cadherin localization remains unknown. A report documents interaction between Bicc1 and SamCystin, another SAM-containing protein, through an unidentified RNA molecule (4). Further studies should reveal whether the Bicc1-SamCystin complex controls EGFR and E-cadherin localization (Figure 2).
|Primers||Primers cannot be located by automatic search.|
Artemis genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change.
Primers for PCR amplification
1) 94°C 2:00
2) 94°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 35X
6) 72°C 5:00
7) 4°C ∞
Primers for sequencing
Bicc1_seq(F): 5’- TTTGAACGTGTGAAAATCTTATCTGT-3’
Bicc1_seq(R): 5’- CCAAACGTGAACAGAACTGAGCTC-3’
The following sequence of 618 nucleotides (from Genbank genomic region NC_000076 for linear DNA sequence of Bicc1) is amplified:
131345 tctgat ggtcctggca acaagctggg ttaattactt gtccatgtac tttgaggtct
131401 tgtttctgtt aagattctgg attcacggag agaacaacac agacttggat gctctcagta
131461 gattaagggc ttaggaaaac acaccccctc ttctccctcg agctttcaaa aagatgtttg
131521 cattgtttta agctgagatc atcttgttgt atcaacacaa agccagaaac atgaaaataa
131581 gaattttttt tttgaacgtg tgaaaatctt atctgtaaat acaagttctt aattgagtca
131641 atatttttct cttgatccct gactcagatc atggaggaga caaacacgca gattgcatgg
131701 ccgtccaaac tgaagatcgg ggctaaatcc aagaaaggta aatttgggac ggggagtagg
131761 tatgtttgaa aaacgagctt ccggggttgc tggagctcag ttctgttcac gtttggcctc
131821 aagtgcttgt caaatagccg tatttgggga ggattttcat gattaaaata aataggtggc
131881 tttgtggcag cagaaaaaaa aatgcttaaa aaaatagtat taaaatagaa atgttaccat
131941 aacgggcttc acagtaacct gt
PCR primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated C is shown in red text.
1. Cogswell, C., Price, S. J., Hou, X., Guay-Woodford, L. M., Flaherty, L., and Bryda, E. C. (2003) Positional cloning of jcpk/bpk locus of the mouse, Mamm. Genome 14, 242-249.
2. Wessely, O., Tran, U., Zakin, L., and De Robertis, E. M. (2001) Identification and expression of the mammalian homologue of Bicaudal-C, Mech. Dev. 101, 267-270.
3. Mohler, J. and Wieschaus, E. F. (1986) Dominant maternal-effect mutations of Drosophila melanogaster causing the production of double-abdomen embryos, Genetics 112, 803-822.
4. Stagner, E. E., Bouvrette, D. J., Cheng, J., and Bryda, E. C. (2009) The polycystic kidney disease-related proteins Bicc1 and SamCystin interact, Biochem. Biophys. Res. Commun. 383, 16-21.
5. Bull, A. (1966) Bicaudal, a genetic factor which affects the polarity of the embryo of Drosophila melanogaster, J. Exp. Zool. 161, 221-242.
6. Ephrussi, A. and Lehmann, R. (1992) Induction of germ cell formation by oskar, Nature 358, 387-392.
7. Gavis, E. R. and Lehmann, R. (1992) Localization of nanos RNA controls embryonic polarity, Cell 71, 301-313.
8. Mahone, M., Saffman, E. E., and Lasko, P. F. (1995) Localized Bicaudal-C RNA encodes a protein containing a KH domain, the RNA binding motif of FMR1, EMBO J. 14, 2043-2055.
9. Saffman, E. E., Styhler, S., Rother, K., Li, W., Richard, S., and Lasko, P. (1998) Premature translation of oskar in oocytes lacking the RNA-binding protein bicaudal-C, Mol. Cell Biol. 18, 4855-4862.
10. Flaherty, L., Messer, A., Russell, L. B., and Rinchik, E. M. (1992) Chlorambucil-induced mutations in mice recovered in homozygotes, Proc. Natl. Acad. Sci. U. S. A 89, 2859-2863.
11. Flaherty, L., Bryda, E. C., Collins, D., Rudofsky, U., and Montogomery, J. C. (1995) New mouse model for polycystic kidney disease with both recessive and dominant gene effects, Kidney Int. 47, 552-558.
12. Guay-Woodford, L. M., Bryda, E. C., Christine, B., Lindsey, J. R., Collier, W. R., Avner, E. D., D'Eustachio, P., and Flaherty, L. (1996) Evidence that two phenotypically distinct mouse PKD mutations, bpk and jcpk, are allelic, Kidney Int. 50, 1158-1165.
13. Ozawa, Y., Nauta, J., Sweeney, W. E., and Avner, E. D. (1993) A new murine model of autosomal recessive polycystic kidney disease, Nippon Jinzo Gakkai Shi 35, 349-354.
14. Nauta, J., Ozawa, Y., Sweeney, W. E., Jr., Rutledge, J. C., and Avner, E. D. (1993) Renal and biliary abnormalities in a new murine model of autosomal recessive polycystic kidney disease, Pediatr. Nephrol. 7, 163-172.
15. Fischer, E., Legue, E., Doyen, A., Nato, F., Nicolas, J. F., Torres, V., Yaniv, M., and Pontoglio, M. (2006) Defective planar cell polarity in polycystic kidney disease, Nat. Genet. 38, 21-23.
16. Simons, M., Gloy, J., Ganner, A., Bullerkotte, A., Bashkurov, M., Kronig, C., Schermer, B., Benzing, T., Cabello, O. A., Jenny, A., Mlodzik, M., Polok, B., Driever, W., Obara, T., and Walz, G. (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways, Nat. Genet. 37, 537-543.
17. Zerres, K., Mucher, G., Becker, J., Steinkamm, C., Rudnik-Schoneborn, S., Heikkila, P., Rapola, J., Salonen, R., Germino, G. G., Onuchic, L., Somlo, S., Avner, E. D., Harman, L. A., Stockwin, J. M., and Guay-Woodford, L. M. (1998) Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology, Am. J. Med. Genet. 76, 137-144.
18. Zerres, K., Rudnik-Schoneborn, S., Steinkamm, C., Becker, J., and Mucher, G. (1998) Autosomal recessive polycystic kidney disease, J. Mol. Med. 76, 303-309.
19. Ward, C. J., Hogan, M. C., Rossetti, S., Walker, D., Sneddon, T., Wang, X., Kubly, V., Cunningham, J. M., Bacallao, R., Ishibashi, M., Milliner, D. S., Torres, V. E., and Harris, P. C. (2002) The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein, Nat. Genet. 30, 259-269.
20. Wheatley, D. N., Wang, A. M., and Strugnell, G. E. (1996) Expression of primary cilia in mammalian cells, Cell Biol. Int. 20, 73-81.
21. Moyer, J. H., Lee-Tischler, M. J., Kwon, H. Y., Schrick, J. J., Avner, E. D., Sweeney, W. E., Godfrey, V. L., Cacheiro, N. L., Wilkinson, J. E., and Woychik, R. P. (1994) , ScienCandidate gene associated with a mutation causing recessive polycystic kidney disease in micece 264, 1329-1333.
22. Sweeney, W. E., Jr. and Avner, E. D. (1998) Functional activity of epidermal growth factor receptors in autosomal recessive polycystic kidney disease, Am. J. Physiol 275, F387-F394.
23. Ryan, S., Verghese, S., Cianciola, N. L., Cotton, C. U., and Carlin, C. R. (2010) Autosomal recessive polycystic kidney disease epithelial cell model reveals multiple basolateral epidermal growth factor receptor sorting pathways, Mol. Biol. Cell 21, 2732-2745.
24. Orellana, S. A., Sweeney, W. E., Neff, C. D., and Avner, E. D. (1995) Epidermal growth factor receptor expression is abnormal in murine polycystic kidney, Kidney Int. 47, 490-499.
25. Du, J. and Wilson, P. D. (1995) Abnormal polarization of EGF receptors and autocrine stimulation of cyst epithelial growth in human ADPKD, Am J. Physiol 269, C487-C495.
26. Wilson, P. D. (2004) A plethora of epidermal growth factor-like proteins in polycystic kidneys, Kidney Int. 65, 2441-2442.
27. Sweeney, W. E., Chen, Y., Nakanishi, K., Frost, P., and Avner, E. D. (2000) Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor, Kidney Int. 57, 33-40.
|Science Writers||Eva Marie Y. Moresco|
|Illustrators||Diantha La Vine|
|Authors||Michael J. Barnes, Amanda L. Blasius, Bruce Beutler|
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