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|Mutation Type||critical splice acceptor site (1 bp from exon)|
|Coordinate||122,173,819 bp (GRCm38)|
|Base Change||C ⇒ A (forward strand)|
|Gene Name||endoplasmic reticulum (ER) to nucleus signalling 2|
|Chromosomal Location||122,169,893-122,186,207 bp (-)|
|MGI Phenotype||PHENOTYPE: Mice homozygous for disruption of this gene are generally normal but display an increased susceptibility to intestinal inflammation. [provided by MGI curators]|
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000033153] [ENSMUSP00000033154] [ENSMUSP00000145716]|
|Predicted Effect||probably null|
|Predicted Effect||probably benign|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2016-11-10 11:50 AM by Anne Murray|
|Record Created||2016-02-17 3:22 PM|
The ernie3 phenotype was identified among G3 mice of the pedigree R1747, some of which exhibited susceptibility to dextran sulfate sodium (DSS)-induced colitis at days 7 (Figure 1) and day 10 (Figure 2) of DSS exposure in the drinking water.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 65 mutations. The increased susceptibility to DSS-induced colitis phenotype was linked to a mutation in Ern2 by continuous variable mapping using gene-based superpedigree analysis in which the Ern2 gene has multiple mutant alleles derived from multiple pedigrees. The Ern2 mutation is a G to T transversion at base pair 122,173,819 (v38) on chromosome 7, or base pair 12,408 in the GenBank genomic region NC_000073 within the acceptor splice site of intron 14. Linkage was found with a recessive model of inheritance (P = 7.934 x 10-17), wherein 13 variant homozygotes from three pedigrees (R0785, R1747, and R4303) departed phenotypically from 27 homozygous reference mice and 46 heterozygous mice (Figure 3).
The effect of the mutation at the cDNA and protein level have not examined, but the mutation is predicted to result in a 2-base pair deletion in exon 15 due to the use of a cryptic site in exon 15. The 2-base pair deletion would result in a frame-shifted protein product beginning after amino acid 525 of the protein, and premature termination after the inclusion of two aberrant amino acids.
Genomic numbering corresponds to NC_000073. The acceptor splice site of intron 14, which is destroyed by the ernie3 mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
Ern2 encodes inositol-requiring enzyme 1β (IRE1β), a type I transmembrane receptor paralog of IRE1α. IRE1β and IRE1α have an N-terminal sensory domain that faces the endoplasmic reticulum (ER) lumen (amino acids 35-426), a transmembrane domain (amino acid 427-447), and a cytoplasmic effector domain at the C-terminus (amino acid 448-911) [Figure 4; (1;2)]. Amino acids 1-33 comprise a signal peptide. The luminal domain (LD) of IRE1β has four pyrrolo-quinoline quinone (PQQ) beta-propeller repeats (amino acids 33-64, 115-147, 148-180, and 192-223; SMART) (3). The cytoplasmic domain of IRE1β has both a protein kinase domain (amino acids 508-768) and a kinase-extension-nuclease domain (KEN domain; alternatively, RNAse domain; amino acids 771-899) (3).
The ernie3 mutation may cause aberrant splicing and subsequent coding of a premature stop codon in exon 15. Exon 15 encodes residues within the kinase domain.
For more information about Ern2, please see the record for ernie.
IRE1β is expressed in the gastrointestinal epithelial cells and mucus cells in bronchial epithelia. During the unfolded protein response (UPR), both IRE1α and IRE1β can catalyze the processing of Xbp1 (4-6), although IRE1β is less efficient than IRE1α (1). IRE1α and IRE1β both activate c-Jun NH2-terminal kinase (JNK) in response to ER stress (7). IRE1β is unique from IRE1α in that IRE1β directly interacts with unfolded proteins rather than with GRP78 during conditions of ER stress (8).
IRE1β posttranscriptionally degrades Mtp (9), which is induced during enterocyte differentiation. Mtp encodes an ER chaperone required for lipid mobilization via apolipoprotein B (apoB) lipoproteins (9). MTP and apoB are also required for chylomicron assembly in the ER of enterocytes (10-12). Chylomicrons are vesicles synthesized by the intestine and function to transport large quantities of dietary fat and fat-soluble vitamins (12-14).
Ern2 knockout (Ern2-/-) mice are viable and healthy. However, when challenged with DSS, the Ern2-/- mice (in both the 129svev and C57BL/6 genetic backgrounds) developed colitis 3-5 days earlier than wild-type and heterozygous mice. In addition, the Ern2-/- mice exhibited mortality approximately 5 days earlier than wild-type or heterozygous mice. Further studies determined that loss of IRE1β expression promotes ER stress specifically in immature goblet cells (15). Examination of goblet cells from Ern2-/- mice determined that the ER was distended in the cells. Within the distended ER of the immature goblet cells, aberrant mucin accumulation was observed. Tsuru et al. proposed that the susceptibility to colitis may indicate a qualitative defect in mucins secreted by the goblet cells in the Ern2-/- mice (15). Similar to the Ern2-/- mice, the ernie3 mice exhibit susceptibility to DSS-induced colitis indicating loss of function in IRE1β.
ernie3(F):5'- AGCTCCAAGGCAATGTAGTGGAAC -3'
ernie3(R):5'- CGTGGTGGGGAAGATTTCCTTCAAC -3'
ernie3_seq(F):5'- TGGAACTGGGGACCATGC -3'
ernie3_seq(R):5'- TTCAACCCCAAGGATGTGCTG -3'
2. Lee, K. P., Dey, M., Neculai, D., Cao, C., Dever, T. E., and Sicheri, F. (2008) Structure of the Dual Enzyme Ire1 Reveals the Basis for Catalysis and Regulation in Nonconventional RNA Splicing. Cell. 132, 89-100.
4. Calfon, M., Zeng, H., Urano, F., Till, J. H., Hubbard, S. R., Harding, H. P., Clark, S. G., and Ron, D. (2002) IRE1 Couples Endoplasmic Reticulum Load to Secretory Capacity by Processing the XBP-1 mRNA. Nature. 415, 92-96.
5. Lee, K., Tirasophon, W., Shen, X., Michalak, M., Prywes, R., Okada, T., Yoshida, H., Mori, K., and Kaufman, R. J. (2002) IRE1-Mediated Unconventional mRNA Splicing and S2P-Mediated ATF6 Cleavage Merge to Regulate XBP1 in Signaling the Unfolded Protein Response. Genes Dev. 16, 452-466.
6. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T., and Mori, K. (2001) XBP1 mRNA is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor. Cell. 107, 881-891.
7. Urano, F., Wang, X., Bertolotti, A., Zhang, Y., Chung, P., Harding, H. P., and Ron, D. (2000) Coupling of Stress in the ER to Activation of JNK Protein Kinases by Transmembrane Protein Kinase IRE1. Science. 287, 664-666.
9. Dai, K., Khatun, I., and Hussain, M. M. (2010) NR2F1 and IRE1beta Suppress Microsomal Triglyceride Transfer Protein Expression and Lipoprotein Assembly in Undifferentiated Intestinal Epithelial Cells. Arterioscler Thromb Vasc Biol. 30, 568-574.
12. Iqbal, J., Dai, K., Seimon, T., Jungreis, R., Oyadomari, M., Kuriakose, G., Ron, D., Tabas, I., and Hussain, M. M. (2008) IRE1beta Inhibits Chylomicron Production by Selectively Degrading MTP mRNA. Cell Metab. 7, 445-455.
13. Hussain, M. M., Kancha, R. K., Zhou, Z., Luchoomun, J., Zu, H., and Bakillah, A. (1996) Chylomicron Assembly and Catabolism: Role of Apolipoproteins and Receptors. Biochim Biophys Acta. 1300, 151-170.
15. Tsuru, A., Fujimoto, N., Takahashi, S., Saito, M., Nakamura, D., Iwano, M., Iwawaki, T., Kadokura, H., Ron, D., and Kohno, K. (2013) Negative Feedback by IRE1beta Optimizes Mucin Production in Goblet Cells. Proc Natl Acad Sci U S A. 110, 2864-2869.
|Science Writers||Anne Murray|
|Illustrators||Peter Jurek, Katherine Timer|
|Authors||Emre Turer, William McAlpine, and Bruce Beutler|
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