Incidental Mutation 'R0006:Erbb3'
| ID |
8045 |
| Institutional Source |
Beutler Lab
|
| Gene Symbol |
Erbb3
|
| Ensembl Gene |
ENSMUSG00000018166 |
| Gene Name |
erb-b2 receptor tyrosine kinase 3 |
| Synonyms |
Erbb3r, Erbb-3, HER3 |
| MMRRC Submission |
041980-MU
|
| Accession Numbers |
|
| Essential gene? |
Essential
(E-score: 1.000)
|
| Stock # |
R0006 (G1)
|
| Quality Score |
|
|
Status
|
Validated
|
| Chromosome |
10 |
| Chromosomal Location |
128403392-128425504 bp(-) (GRCm39) |
| Type of Mutation |
critical splice donor site (2 bp from exon) |
| DNA Base Change (assembly) |
A to G
at 128409279 bp (GRCm39)
|
| Zygosity |
Heterozygous |
| Amino Acid Change |
|
| Ref Sequence |
ENSEMBL: ENSMUSP00000080716
(fasta)
|
| Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000082059]
|
| AlphaFold |
Q61526 |
| Predicted Effect |
probably null
Transcript: ENSMUST00000082059
|
| SMART Domains |
Protein: ENSMUSP00000080716
Gene: ENSMUSG00000018166
| Domain | Start | End | E-Value | Type |
|---|
|
signal peptide
|
1 |
19 |
N/A |
INTRINSIC |
|
Pfam:Recep_L_domain
|
55 |
167 |
2.4e-31 |
PFAM |
|
FU
|
180 |
220 |
5.83e0 |
SMART |
|
FU
|
223 |
265 |
7.63e-10 |
SMART |
|
Pfam:Recep_L_domain
|
353 |
474 |
7.5e-33 |
PFAM |
|
FU
|
490 |
541 |
7.82e-7 |
SMART |
|
FU
|
546 |
595 |
1.34e-5 |
SMART |
|
FU
|
607 |
643 |
9.24e0 |
SMART |
|
TyrKc
|
707 |
963 |
7.42e-91 |
SMART |
|
low complexity region
|
997 |
1018 |
N/A |
INTRINSIC |
|
low complexity region
|
1113 |
1124 |
N/A |
INTRINSIC |
|
low complexity region
|
1135 |
1148 |
N/A |
INTRINSIC |
|
low complexity region
|
1172 |
1185 |
N/A |
INTRINSIC |
|
low complexity region
|
1186 |
1196 |
N/A |
INTRINSIC |
|
low complexity region
|
1201 |
1213 |
N/A |
INTRINSIC |
|
| Meta Mutation Damage Score |
0.9482 |
| Coding Region Coverage |
- 1x: 77.9%
- 3x: 66.3%
- 10x: 36.9%
- 20x: 17.4%
|
| Validation Efficiency |
95% (74/78) |
| MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized. [provided by RefSeq, Jul 2008]
PHENOTYPE: Homozygotes for targeted null mutations exhibit a lack of Schwann-cell precursors leading to loss of sensory and motor neurons, hypoplasia of the primary sympathetic ganglion chain, cardiac defects, impaired brain development, and embryonic lethality. [provided by MGI curators]
|
| Allele List at MGI |
All alleles(27) : Targeted(11) Gene trapped(14) Chemically induced(2)
|
| Other mutations in this stock |
Total: 26 list
| Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
|---|
| Appl2 |
A |
G |
10: 83,438,762 (GRCm39) |
F556L |
probably damaging |
Het |
| Atad2b |
T |
A |
12: 4,992,030 (GRCm39) |
S210T |
possibly damaging |
Het |
| Aurka |
A |
G |
2: 172,201,673 (GRCm39) |
|
probably null |
Het |
| Chd8 |
A |
G |
14: 52,472,750 (GRCm39) |
I351T |
possibly damaging |
Het |
| Chid1 |
T |
A |
7: 141,076,339 (GRCm39) |
|
probably benign |
Het |
| Dnase2b |
T |
A |
3: 146,288,244 (GRCm39) |
I284F |
probably damaging |
Het |
| Dst |
C |
T |
1: 34,267,999 (GRCm39) |
T5325I |
probably benign |
Het |
| Fancl |
A |
G |
11: 26,419,695 (GRCm39) |
N316S |
possibly damaging |
Het |
| Gabrd |
C |
A |
4: 155,473,058 (GRCm39) |
V72L |
probably damaging |
Het |
| Hephl1 |
T |
A |
9: 14,988,060 (GRCm39) |
T683S |
probably benign |
Het |
| Jazf1 |
A |
G |
6: 52,871,071 (GRCm39) |
|
probably benign |
Het |
| Kntc1 |
T |
A |
5: 123,927,201 (GRCm39) |
S1219T |
probably benign |
Het |
| L3mbtl1 |
A |
T |
2: 162,806,489 (GRCm39) |
Y460F |
possibly damaging |
Het |
| Map1b |
C |
T |
13: 99,571,810 (GRCm39) |
V304M |
probably damaging |
Het |
| Msantd4 |
A |
G |
9: 4,384,099 (GRCm39) |
E140G |
probably damaging |
Het |
| Myo16 |
A |
G |
8: 10,525,988 (GRCm39) |
K843E |
probably damaging |
Het |
| Rap1gds1 |
G |
T |
3: 138,689,632 (GRCm39) |
|
probably null |
Het |
| Rsph4a |
T |
C |
10: 33,785,144 (GRCm39) |
C148R |
probably damaging |
Het |
| Slc7a9 |
A |
T |
7: 35,169,525 (GRCm39) |
|
probably benign |
Het |
| Sptbn1 |
A |
G |
11: 30,073,855 (GRCm39) |
S1405P |
probably damaging |
Het |
| Tex35 |
T |
C |
1: 156,927,314 (GRCm39) |
K154E |
possibly damaging |
Het |
| Tpm3 |
T |
A |
3: 89,994,968 (GRCm39) |
|
probably benign |
Het |
| Ubr4 |
T |
C |
4: 139,158,960 (GRCm39) |
F2438L |
probably benign |
Het |
| Wfdc8 |
T |
C |
2: 164,440,984 (GRCm39) |
D253G |
probably damaging |
Het |
| Zfp451 |
A |
T |
1: 33,841,861 (GRCm39) |
|
probably benign |
Het |
| Zfp687 |
A |
G |
3: 94,918,767 (GRCm39) |
I335T |
probably damaging |
Het |
|
| Other mutations in Erbb3 |
| Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
|---|
|
IGL00659:Erbb3
|
APN |
10 |
128,406,852 (GRCm39) |
missense |
probably damaging |
0.99 |
|
IGL01482:Erbb3
|
APN |
10 |
128,408,798 (GRCm39) |
missense |
possibly damaging |
0.87 |
|
IGL01866:Erbb3
|
APN |
10 |
128,405,237 (GRCm39) |
makesense |
probably null |
|
|
IGL01981:Erbb3
|
APN |
10 |
128,407,519 (GRCm39) |
missense |
probably benign |
0.28 |
|
IGL02190:Erbb3
|
APN |
10 |
128,406,879 (GRCm39) |
splice site |
probably null |
|
|
IGL02329:Erbb3
|
APN |
10 |
128,409,088 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL02400:Erbb3
|
APN |
10 |
128,415,393 (GRCm39) |
missense |
probably benign |
0.02 |
|
IGL02478:Erbb3
|
APN |
10 |
128,407,227 (GRCm39) |
nonsense |
probably null |
|
|
IGL02502:Erbb3
|
APN |
10 |
128,406,153 (GRCm39) |
missense |
probably benign |
|
|
IGL02539:Erbb3
|
APN |
10 |
128,420,174 (GRCm39) |
splice site |
probably null |
|
|
IGL03187:Erbb3
|
APN |
10 |
128,408,463 (GRCm39) |
splice site |
probably benign |
|
|
I1329:Erbb3
|
UTSW |
10 |
128,419,323 (GRCm39) |
missense |
possibly damaging |
0.73 |
|
PIT4812001:Erbb3
|
UTSW |
10 |
128,410,248 (GRCm39) |
missense |
possibly damaging |
0.67 |
|
R0006:Erbb3
|
UTSW |
10 |
128,409,279 (GRCm39) |
critical splice donor site |
probably null |
|
|
R0078:Erbb3
|
UTSW |
10 |
128,419,310 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R0366:Erbb3
|
UTSW |
10 |
128,408,439 (GRCm39) |
missense |
possibly damaging |
0.77 |
|
R0601:Erbb3
|
UTSW |
10 |
128,412,881 (GRCm39) |
missense |
probably benign |
0.01 |
|
R0621:Erbb3
|
UTSW |
10 |
128,422,094 (GRCm39) |
missense |
probably benign |
0.00 |
|
R1222:Erbb3
|
UTSW |
10 |
128,407,534 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1675:Erbb3
|
UTSW |
10 |
128,407,073 (GRCm39) |
missense |
probably damaging |
0.97 |
|
R1676:Erbb3
|
UTSW |
10 |
128,419,117 (GRCm39) |
missense |
probably benign |
0.08 |
|
R1692:Erbb3
|
UTSW |
10 |
128,407,594 (GRCm39) |
missense |
probably benign |
0.19 |
|
R1875:Erbb3
|
UTSW |
10 |
128,410,335 (GRCm39) |
missense |
possibly damaging |
0.71 |
|
R2002:Erbb3
|
UTSW |
10 |
128,422,094 (GRCm39) |
missense |
probably benign |
0.00 |
|
R2219:Erbb3
|
UTSW |
10 |
128,405,740 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R2328:Erbb3
|
UTSW |
10 |
128,419,562 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R3840:Erbb3
|
UTSW |
10 |
128,406,193 (GRCm39) |
missense |
probably benign |
|
|
R4393:Erbb3
|
UTSW |
10 |
128,408,639 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R4567:Erbb3
|
UTSW |
10 |
128,414,944 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R4616:Erbb3
|
UTSW |
10 |
128,408,639 (GRCm39) |
nonsense |
probably null |
|
|
R4766:Erbb3
|
UTSW |
10 |
128,422,107 (GRCm39) |
missense |
possibly damaging |
0.76 |
|
R4881:Erbb3
|
UTSW |
10 |
128,412,816 (GRCm39) |
missense |
probably benign |
0.00 |
|
R4974:Erbb3
|
UTSW |
10 |
128,408,317 (GRCm39) |
missense |
probably benign |
|
|
R5266:Erbb3
|
UTSW |
10 |
128,405,505 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R5463:Erbb3
|
UTSW |
10 |
128,405,948 (GRCm39) |
nonsense |
probably null |
|
|
R5481:Erbb3
|
UTSW |
10 |
128,408,349 (GRCm39) |
missense |
probably damaging |
0.98 |
|
R5997:Erbb3
|
UTSW |
10 |
128,419,054 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R6370:Erbb3
|
UTSW |
10 |
128,405,943 (GRCm39) |
missense |
possibly damaging |
0.90 |
|
R7639:Erbb3
|
UTSW |
10 |
128,405,716 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R7713:Erbb3
|
UTSW |
10 |
128,410,318 (GRCm39) |
missense |
probably benign |
|
|
R7847:Erbb3
|
UTSW |
10 |
128,407,058 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R8529:Erbb3
|
UTSW |
10 |
128,419,069 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R8843:Erbb3
|
UTSW |
10 |
128,414,325 (GRCm39) |
missense |
possibly damaging |
0.82 |
|
R8988:Erbb3
|
UTSW |
10 |
128,406,030 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R9336:Erbb3
|
UTSW |
10 |
128,420,929 (GRCm39) |
missense |
probably benign |
0.15 |
|
R9530:Erbb3
|
UTSW |
10 |
128,410,291 (GRCm39) |
missense |
probably benign |
|
|
| Protein Function and Prediction |
ERBB3 is a member of the epidermal growth factor receptor (EGFR) family and an activator of the phosphatidylinositol-3-kinase/Akt pathway [reviewed in (1)]. It regulates cell survival and vesicle trafficking and is essential for the generation of precursors of Schwann cells that normally accompany peripheral axons of motor neurons (OMIM: *190151). ERBB3 expression has been linked to many cancers including breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung [(2); reviewed in (1)]. Neuregulins are among the ligands for ERBB3 and the ligand-receptors are involved in maintenance of cell division, proliferation, differentiation, and migration [reviewed in (1)].
|
| Expression/Localization |
ERBB3 mRNA is present from the earliest stages of development and ERBB3 is widely expressed in human adult tissues, consistently detected in brain, spinal cord, liver, prostate, kidney and lung [reviewed in (1)].
|
| Background |
Mutations in ERBB3 are linked to Lethal congenital contractural syndrome 2 [LCCS2; OMIM: #607598; (3)], a condition marked by specific neuropathology with degeneration of anterior horn neurons, and extreme skeletal muscle atrophy (4). Most of the infants with LCCS2 died shortly after birth (4). As early as 15 weeks gestation researchers noted fetal akinesia, limb contractures, hydramnios, and distended urinary bladder (4).
Erbb3tm1.1Dwt/tm1.1Dwt; MGI:3513098
either: 129S6/SvEvTac-Erbb3tm1.1Dwt or B6.129S6-Erbb3tm1.1Dwt
Homozygous animals die by 3 weeks of age and exhibit partial lethality throughout fetal growth and development (5).
Erbb3tm1Cbm/tm1Cbm; MGI:1929072
either: 129P2/OlaHsd or (involves: 129P2/OlaHsd * C57BL/6)
Homozygous animals exhibit complete perinatal lethality, with most animals dying around E11.5 and E13.5. Pups do not respond to tactile stimuli, have increased neuron apoptosis, neuron degeneration, and respiratory failure (6).
Erbb3tm1Gne/tm1Gne; MGI: 1928828
involves: 129S2/SvPas * C57BL/6
Homozygous mice die by E10.5 and exhibit abnormal pancreas morphology, abnormal heart development and morphology, poor circulation, and abnormal brain development (7).
Erbb3tm2Cbm/tm2Cbm; MGI:1929598
either: 129P2/OlaHsd or (involves: 129P2/OlaHsd * C57BL/6)
Homozygous animals exhibit complete perinatal lethality, with most animals dying around E11.5 and E13.5. Pups do not respond to tactile stimuli, have increased neuron apoptosis, neuron degeneration, and respiratory failure (6).
Erbb3tm2Cbm/tm2Cbm; MGI:1929598
involves: 129P2/OlaHsd
Adrenergic chromaffin cells are absent in the medulla of homozygous animals. Furthermore, homozygous animals have abnormal sympathetic system morphology, small superior cervical ganglion, abnormal adrenal gland morphology, abnormal neural crest migration, and a reduction in noradrenaline levels (8).
|
| References |
3. Narkis, G., Ofir, R., Manor, E., Landau, D., Elbedour, K., and Birk, O. S. (2007) Lethal Congenital Contractural Syndrome Type 2 (LCCS2) is Caused by a Mutation in ERBB3 (Her3), a Modulator of the Phosphatidylinositol-3-kinase/Akt Pathway. Am J Hum Genet. 81, 589-595.
4. Landau, D., Mishori-Dery, A., Hershkovitz, R., Narkis, G., Elbedour, K., and Carmi, R. (2003) A New Autosomal Recessive Congenital Contractural Syndrome in an Israeli Bedouin Kindred. Am J Med Genet A. 117A, 37-40.
5. Lee, D., Yu, M., Lee, E., Kim, H., Yang, Y., Kim, K., Pannicia, C., Kurie, J. M., and Threadgill, D. W. (2009) Tumor-Specific Apoptosis Caused by Deletion of the ERBB3 Pseudo-Kinase in Mouse Intestinal Epithelium. J Clin Invest. 119, 2702-2713.
6. Riethmacher, D., Sonnenberg-Riethmacher, E., Brinkmann, V., Yamaai, T., Lewin, G. R., and Birchmeier, C. (1997) Severe Neuropathies in Mice with Targeted Mutations in the ErbB3 Receptor. Nature. 389, 725-730.
7. Erickson, S. L., O'Shea, K. S., Ghaboosi, N., Loverro, L., Frantz, G., Bauer, M., Lu, L. H., and Moore, M. W. (1997) ErbB3 is Required for Normal Cerebellar and Cardiac Development: A Comparison with ErbB2-and Heregulin-Deficient Mice. Development. 124, 4999-5011.
8. Britsch, S., Li, L., Kirchhoff, S., Theuring, F., Brinkmann, V., Birchmeier, C., and Riethmacher, D. (1998) The ErbB2 and ErbB3 Receptors and their Ligand, Neuregulin-1, are Essential for Development of the Sympathetic Nervous System. Genes Dev. 12, 1825-1836. |
| Posted On |
2012-11-20 |
| Science Writer |
Anne Murray |
Incidental Mutation