Phenotypic Mutation 'oscar' (pdf version)
Allele | oscar |
Mutation Type |
nonsense
|
Chromosome | 3 |
Coordinate | 86,257,611 bp (GRCm39) |
Base Change | C ⇒ T (forward strand) |
Gene |
Lrba
|
Gene Name | LPS-responsive beige-like anchor |
Synonym(s) | Lba, D3Ertd775e |
Chromosomal Location |
86,131,987-86,689,999 bp (+) (GRCm39)
|
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a member of the WDL-BEACH-WD (WBW) gene family. Its expression is induced in B cells and macrophages by bacterial lipopolysaccharides (LPS). The encoded protein associates with protein kinase A and may be involved in leading intracellular vesicles to activated receptor complexes, which aids in the secretion and/or membrane deposition of immune effector molecules. Defects in this gene are associated with the disorder common variable immunodeficiency-8 with autoimmunity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012] PHENOTYPE: Mice homozygous for a knock-out allele exhibit increased numbers of myeloid-derived suppressor cells and regulatory T cells, abnormal NK cell physiology, impaired rejection of allogeneic, xenogeneic and missing self bone-marrow grafts, and resistance to acute graft vs host disease. [provided by MGI curators]
|
Accession Number | NCBI RefSeq: NM_030695, NM_001077688, NM_001077687; MGI: 1933162
|
Mapped | Yes |
Amino Acid Change |
Glutamine changed to Stop codon
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000103261]
[ENSMUSP00000142179]
[ENSMUSP00000142043]
[ENSMUSP00000148618]
|
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000103261 Gene: ENSMUSG00000028080 AA Change: Q1292*
Domain | Start | End | E-Value | Type |
low complexity region
|
12 |
31 |
N/A |
INTRINSIC |
Pfam:Laminin_G_3
|
211 |
377 |
4.6e-13 |
PFAM |
Pfam:DUF4704
|
446 |
717 |
2.5e-109 |
PFAM |
coiled coil region
|
1019 |
1037 |
N/A |
INTRINSIC |
low complexity region
|
1073 |
1089 |
N/A |
INTRINSIC |
low complexity region
|
1100 |
1113 |
N/A |
INTRINSIC |
low complexity region
|
1585 |
1600 |
N/A |
INTRINSIC |
low complexity region
|
1614 |
1630 |
N/A |
INTRINSIC |
low complexity region
|
1698 |
1713 |
N/A |
INTRINSIC |
low complexity region
|
1738 |
1757 |
N/A |
INTRINSIC |
low complexity region
|
1848 |
1861 |
N/A |
INTRINSIC |
Pfam:DUF1088
|
1882 |
2049 |
7e-88 |
PFAM |
Pfam:PH_BEACH
|
2075 |
2172 |
9.1e-31 |
PFAM |
Beach
|
2203 |
2480 |
2.87e-207 |
SMART |
WD40
|
2578 |
2615 |
7.4e0 |
SMART |
WD40
|
2618 |
2661 |
1.72e0 |
SMART |
WD40
|
2677 |
2716 |
3.99e-1 |
SMART |
WD40
|
2760 |
2798 |
1.79e-1 |
SMART |
WD40
|
2801 |
2840 |
4.28e0 |
SMART |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000142179 Gene: ENSMUSG00000028080 AA Change: Q1292*
Domain | Start | End | E-Value | Type |
low complexity region
|
12 |
31 |
N/A |
INTRINSIC |
Pfam:Laminin_G_3
|
205 |
377 |
7.4e-18 |
PFAM |
coiled coil region
|
1019 |
1037 |
N/A |
INTRINSIC |
low complexity region
|
1073 |
1089 |
N/A |
INTRINSIC |
low complexity region
|
1100 |
1113 |
N/A |
INTRINSIC |
low complexity region
|
1585 |
1600 |
N/A |
INTRINSIC |
low complexity region
|
1614 |
1630 |
N/A |
INTRINSIC |
low complexity region
|
1698 |
1713 |
N/A |
INTRINSIC |
low complexity region
|
1738 |
1757 |
N/A |
INTRINSIC |
low complexity region
|
1848 |
1861 |
N/A |
INTRINSIC |
Pfam:DUF1088
|
1882 |
2050 |
1.5e-92 |
PFAM |
Pfam:PH_BEACH
|
2068 |
2172 |
7.5e-32 |
PFAM |
Beach
|
2203 |
2480 |
2.87e-207 |
SMART |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000142043 Gene: ENSMUSG00000028080 AA Change: Q1292*
Domain | Start | End | E-Value | Type |
low complexity region
|
12 |
31 |
N/A |
INTRINSIC |
Pfam:Laminin_G_3
|
205 |
377 |
8.1e-18 |
PFAM |
coiled coil region
|
1019 |
1037 |
N/A |
INTRINSIC |
low complexity region
|
1073 |
1089 |
N/A |
INTRINSIC |
low complexity region
|
1100 |
1113 |
N/A |
INTRINSIC |
low complexity region
|
1585 |
1600 |
N/A |
INTRINSIC |
low complexity region
|
1614 |
1630 |
N/A |
INTRINSIC |
low complexity region
|
1698 |
1713 |
N/A |
INTRINSIC |
low complexity region
|
1738 |
1757 |
N/A |
INTRINSIC |
low complexity region
|
1848 |
1861 |
N/A |
INTRINSIC |
Pfam:DUF1088
|
1882 |
2050 |
1.6e-92 |
PFAM |
Pfam:PH_BEACH
|
2068 |
2172 |
8.3e-32 |
PFAM |
Beach
|
2203 |
2480 |
2.87e-207 |
SMART |
WD40
|
2578 |
2615 |
7.4e0 |
SMART |
WD40
|
2618 |
2661 |
1.72e0 |
SMART |
WD40
|
2677 |
2716 |
3.99e-1 |
SMART |
|
Predicted Effect |
probably null
|
Predicted Effect |
probably null
|
Meta Mutation Damage Score |
0.9713 |
Is this an essential gene? |
Non Essential (E-score: 0.000) |
Phenotypic Category |
Autosomal Recessive |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All mutations/alleles(13) : Chemically induced (other)(1) Gene trapped(10) Radiation induced(1) Targeted(1)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00420:Lrba
|
APN |
3 |
86267089 |
missense |
probably benign |
0.00 |
IGL00788:Lrba
|
APN |
3 |
86234992 |
missense |
probably damaging |
0.97 |
IGL01139:Lrba
|
APN |
3 |
86549969 |
missense |
possibly damaging |
0.88 |
IGL01302:Lrba
|
APN |
3 |
86202707 |
missense |
probably damaging |
1.00 |
IGL01612:Lrba
|
APN |
3 |
86683484 |
missense |
possibly damaging |
0.89 |
IGL01718:Lrba
|
APN |
3 |
86258555 |
missense |
probably damaging |
1.00 |
IGL01719:Lrba
|
APN |
3 |
86234903 |
splice site |
probably benign |
|
IGL01730:Lrba
|
APN |
3 |
86648731 |
missense |
possibly damaging |
0.89 |
IGL01735:Lrba
|
APN |
3 |
86234968 |
missense |
probably benign |
0.28 |
IGL01875:Lrba
|
APN |
3 |
86217354 |
missense |
probably damaging |
1.00 |
IGL01884:Lrba
|
APN |
3 |
86217719 |
missense |
possibly damaging |
0.86 |
IGL02264:Lrba
|
APN |
3 |
86687569 |
missense |
probably damaging |
0.99 |
IGL02638:Lrba
|
APN |
3 |
86232380 |
missense |
probably damaging |
0.97 |
IGL02647:Lrba
|
APN |
3 |
86267038 |
missense |
probably benign |
0.00 |
IGL02664:Lrba
|
APN |
3 |
86233038 |
missense |
possibly damaging |
0.84 |
IGL02728:Lrba
|
APN |
3 |
86683356 |
missense |
probably damaging |
0.99 |
IGL02730:Lrba
|
APN |
3 |
86235506 |
missense |
probably damaging |
1.00 |
IGL02883:Lrba
|
APN |
3 |
86352720 |
missense |
probably damaging |
0.99 |
IGL02883:Lrba
|
APN |
3 |
86261513 |
missense |
probably damaging |
1.00 |
IGL02948:Lrba
|
APN |
3 |
86217691 |
splice site |
probably null |
|
IGL03090:Lrba
|
APN |
3 |
86680448 |
missense |
probably benign |
0.01 |
molasses
|
UTSW |
3 |
86261614 |
critical splice donor site |
probably null |
|
oscar2
|
UTSW |
3 |
86571765 |
nonsense |
probably null |
|
P0023:Lrba
|
UTSW |
3 |
86325242 |
missense |
probably damaging |
1.00 |
PIT4802001:Lrba
|
UTSW |
3 |
86571801 |
nonsense |
probably null |
|
R0077:Lrba
|
UTSW |
3 |
86449995 |
missense |
probably damaging |
0.99 |
R0189:Lrba
|
UTSW |
3 |
86275816 |
missense |
probably damaging |
1.00 |
R0217:Lrba
|
UTSW |
3 |
86550029 |
missense |
probably damaging |
1.00 |
R0349:Lrba
|
UTSW |
3 |
86447312 |
missense |
probably damaging |
1.00 |
R0396:Lrba
|
UTSW |
3 |
86202486 |
missense |
probably damaging |
1.00 |
R0417:Lrba
|
UTSW |
3 |
86622961 |
missense |
probably damaging |
1.00 |
R0536:Lrba
|
UTSW |
3 |
86622839 |
missense |
probably damaging |
1.00 |
R0712:Lrba
|
UTSW |
3 |
86205297 |
nonsense |
probably null |
|
R0722:Lrba
|
UTSW |
3 |
86513296 |
critical splice donor site |
probably null |
|
R0828:Lrba
|
UTSW |
3 |
86515677 |
splice site |
probably null |
|
R0927:Lrba
|
UTSW |
3 |
86687540 |
missense |
probably damaging |
1.00 |
R1120:Lrba
|
UTSW |
3 |
86202499 |
missense |
probably damaging |
1.00 |
R1141:Lrba
|
UTSW |
3 |
86526865 |
missense |
probably damaging |
1.00 |
R1276:Lrba
|
UTSW |
3 |
86571833 |
missense |
probably damaging |
1.00 |
R1449:Lrba
|
UTSW |
3 |
86261585 |
missense |
probably damaging |
1.00 |
R1470:Lrba
|
UTSW |
3 |
86644449 |
missense |
probably damaging |
1.00 |
R1470:Lrba
|
UTSW |
3 |
86644449 |
missense |
probably damaging |
1.00 |
R1474:Lrba
|
UTSW |
3 |
86687573 |
splice site |
probably benign |
|
R1558:Lrba
|
UTSW |
3 |
86258622 |
missense |
probably damaging |
1.00 |
R1596:Lrba
|
UTSW |
3 |
86257611 |
nonsense |
probably null |
|
R1652:Lrba
|
UTSW |
3 |
86447245 |
missense |
probably damaging |
1.00 |
R1800:Lrba
|
UTSW |
3 |
86259175 |
missense |
probably benign |
0.00 |
R1819:Lrba
|
UTSW |
3 |
86449941 |
missense |
possibly damaging |
0.80 |
R1862:Lrba
|
UTSW |
3 |
86680510 |
critical splice donor site |
probably null |
|
R1917:Lrba
|
UTSW |
3 |
86571808 |
missense |
probably damaging |
1.00 |
R1965:Lrba
|
UTSW |
3 |
86513175 |
critical splice acceptor site |
probably null |
|
R1966:Lrba
|
UTSW |
3 |
86513175 |
critical splice acceptor site |
probably null |
|
R1969:Lrba
|
UTSW |
3 |
86515696 |
missense |
probably damaging |
0.99 |
R2011:Lrba
|
UTSW |
3 |
86217324 |
missense |
probably damaging |
0.99 |
R2179:Lrba
|
UTSW |
3 |
86261588 |
missense |
probably damaging |
1.00 |
R2186:Lrba
|
UTSW |
3 |
86211643 |
missense |
probably damaging |
1.00 |
R2281:Lrba
|
UTSW |
3 |
86683410 |
missense |
possibly damaging |
0.46 |
R2359:Lrba
|
UTSW |
3 |
86256057 |
missense |
probably benign |
0.01 |
R2412:Lrba
|
UTSW |
3 |
86235007 |
missense |
probably damaging |
1.00 |
R2496:Lrba
|
UTSW |
3 |
86439394 |
missense |
probably damaging |
1.00 |
R3153:Lrba
|
UTSW |
3 |
86192526 |
missense |
probably damaging |
0.99 |
R3708:Lrba
|
UTSW |
3 |
86192331 |
missense |
possibly damaging |
0.80 |
R3746:Lrba
|
UTSW |
3 |
86283260 |
missense |
probably damaging |
1.00 |
R3747:Lrba
|
UTSW |
3 |
86283260 |
missense |
probably damaging |
1.00 |
R3748:Lrba
|
UTSW |
3 |
86283260 |
missense |
probably damaging |
1.00 |
R3749:Lrba
|
UTSW |
3 |
86283260 |
missense |
probably damaging |
1.00 |
R3750:Lrba
|
UTSW |
3 |
86283260 |
missense |
probably damaging |
1.00 |
R3758:Lrba
|
UTSW |
3 |
86683356 |
missense |
probably damaging |
0.99 |
R3975:Lrba
|
UTSW |
3 |
86258562 |
missense |
probably damaging |
1.00 |
R4210:Lrba
|
UTSW |
3 |
86267433 |
missense |
probably damaging |
1.00 |
R4258:Lrba
|
UTSW |
3 |
86352656 |
missense |
probably damaging |
1.00 |
R4657:Lrba
|
UTSW |
3 |
86644471 |
missense |
probably damaging |
1.00 |
R4713:Lrba
|
UTSW |
3 |
86267175 |
missense |
probably benign |
0.13 |
R4716:Lrba
|
UTSW |
3 |
86550021 |
missense |
probably damaging |
0.99 |
R4811:Lrba
|
UTSW |
3 |
86683448 |
missense |
probably damaging |
1.00 |
R4827:Lrba
|
UTSW |
3 |
86267457 |
missense |
possibly damaging |
0.85 |
R4840:Lrba
|
UTSW |
3 |
86526816 |
critical splice acceptor site |
probably null |
|
R4920:Lrba
|
UTSW |
3 |
86571765 |
nonsense |
probably null |
|
R4948:Lrba
|
UTSW |
3 |
86192335 |
missense |
probably damaging |
1.00 |
R4970:Lrba
|
UTSW |
3 |
86132678 |
missense |
probably benign |
0.23 |
R4985:Lrba
|
UTSW |
3 |
86234743 |
splice site |
probably null |
|
R4993:Lrba
|
UTSW |
3 |
86267344 |
missense |
probably damaging |
1.00 |
R5107:Lrba
|
UTSW |
3 |
86267086 |
missense |
possibly damaging |
0.47 |
R5112:Lrba
|
UTSW |
3 |
86132678 |
missense |
probably benign |
0.23 |
R5122:Lrba
|
UTSW |
3 |
86256461 |
nonsense |
probably null |
|
R5155:Lrba
|
UTSW |
3 |
86258607 |
missense |
probably benign |
0.25 |
R5194:Lrba
|
UTSW |
3 |
86235526 |
missense |
probably damaging |
1.00 |
R5280:Lrba
|
UTSW |
3 |
86232329 |
missense |
possibly damaging |
0.94 |
R5445:Lrba
|
UTSW |
3 |
86275902 |
missense |
probably benign |
|
R5469:Lrba
|
UTSW |
3 |
86449948 |
missense |
probably damaging |
1.00 |
R5513:Lrba
|
UTSW |
3 |
86449948 |
missense |
probably damaging |
1.00 |
R5578:Lrba
|
UTSW |
3 |
86664814 |
missense |
probably benign |
0.27 |
R5740:Lrba
|
UTSW |
3 |
86235649 |
missense |
probably damaging |
1.00 |
R5868:Lrba
|
UTSW |
3 |
86226911 |
missense |
probably damaging |
1.00 |
R6104:Lrba
|
UTSW |
3 |
86261099 |
missense |
probably damaging |
1.00 |
R6166:Lrba
|
UTSW |
3 |
86261614 |
critical splice donor site |
probably null |
|
R6279:Lrba
|
UTSW |
3 |
86256171 |
missense |
probably benign |
0.26 |
R6330:Lrba
|
UTSW |
3 |
86255664 |
missense |
probably benign |
0.07 |
R6367:Lrba
|
UTSW |
3 |
86275869 |
missense |
probably benign |
0.42 |
R6571:Lrba
|
UTSW |
3 |
86267367 |
missense |
probably damaging |
1.00 |
R6584:Lrba
|
UTSW |
3 |
86571883 |
missense |
probably damaging |
1.00 |
R6698:Lrba
|
UTSW |
3 |
86211732 |
missense |
probably damaging |
0.99 |
R6763:Lrba
|
UTSW |
3 |
86261570 |
missense |
probably damaging |
1.00 |
R6834:Lrba
|
UTSW |
3 |
86257593 |
missense |
probably benign |
0.00 |
R6951:Lrba
|
UTSW |
3 |
86653180 |
missense |
probably benign |
0.01 |
R6969:Lrba
|
UTSW |
3 |
86526897 |
missense |
probably benign |
0.21 |
R7045:Lrba
|
UTSW |
3 |
86192398 |
missense |
probably benign |
0.03 |
R7133:Lrba
|
UTSW |
3 |
86302238 |
splice site |
probably null |
|
R7182:Lrba
|
UTSW |
3 |
86648765 |
frame shift |
probably null |
|
R7214:Lrba
|
UTSW |
3 |
86235633 |
missense |
probably damaging |
1.00 |
R7224:Lrba
|
UTSW |
3 |
86302553 |
missense |
probably damaging |
1.00 |
R7243:Lrba
|
UTSW |
3 |
86658823 |
splice site |
probably null |
|
R7350:Lrba
|
UTSW |
3 |
86259209 |
missense |
probably damaging |
0.96 |
R7380:Lrba
|
UTSW |
3 |
86232381 |
missense |
probably damaging |
1.00 |
R7492:Lrba
|
UTSW |
3 |
86571835 |
missense |
probably damaging |
1.00 |
R7651:Lrba
|
UTSW |
3 |
86648773 |
nonsense |
probably null |
|
R7729:Lrba
|
UTSW |
3 |
86225474 |
missense |
probably damaging |
1.00 |
R7754:Lrba
|
UTSW |
3 |
86352704 |
missense |
probably damaging |
1.00 |
R7762:Lrba
|
UTSW |
3 |
86439508 |
missense |
probably damaging |
0.99 |
R7855:Lrba
|
UTSW |
3 |
86222737 |
missense |
possibly damaging |
0.94 |
R7867:Lrba
|
UTSW |
3 |
86275896 |
missense |
probably damaging |
1.00 |
R7912:Lrba
|
UTSW |
3 |
86622872 |
missense |
probably damaging |
1.00 |
R7995:Lrba
|
UTSW |
3 |
86526858 |
missense |
probably damaging |
1.00 |
R8013:Lrba
|
UTSW |
3 |
86325278 |
missense |
probably damaging |
1.00 |
R8014:Lrba
|
UTSW |
3 |
86325278 |
missense |
probably damaging |
1.00 |
R8024:Lrba
|
UTSW |
3 |
86202708 |
nonsense |
probably null |
|
R8027:Lrba
|
UTSW |
3 |
86325219 |
missense |
probably benign |
0.05 |
R8090:Lrba
|
UTSW |
3 |
86255796 |
missense |
probably benign |
|
R8111:Lrba
|
UTSW |
3 |
86235012 |
missense |
probably damaging |
1.00 |
R8118:Lrba
|
UTSW |
3 |
86261533 |
missense |
probably benign |
|
R8204:Lrba
|
UTSW |
3 |
86222710 |
missense |
possibly damaging |
0.95 |
R8239:Lrba
|
UTSW |
3 |
86449882 |
missense |
probably damaging |
1.00 |
R8509:Lrba
|
UTSW |
3 |
86255483 |
missense |
probably benign |
0.04 |
R8532:Lrba
|
UTSW |
3 |
86664790 |
missense |
probably damaging |
1.00 |
R8726:Lrba
|
UTSW |
3 |
86261062 |
missense |
probably benign |
|
R8744:Lrba
|
UTSW |
3 |
86211640 |
missense |
probably benign |
0.08 |
R8782:Lrba
|
UTSW |
3 |
86549976 |
missense |
probably benign |
0.00 |
R8784:Lrba
|
UTSW |
3 |
86283235 |
missense |
probably damaging |
1.00 |
R8922:Lrba
|
UTSW |
3 |
86263973 |
missense |
probably damaging |
1.00 |
R8964:Lrba
|
UTSW |
3 |
86258552 |
missense |
probably benign |
0.22 |
R8971:Lrba
|
UTSW |
3 |
86522388 |
missense |
probably benign |
0.00 |
R9046:Lrba
|
UTSW |
3 |
86302543 |
missense |
possibly damaging |
0.94 |
R9155:Lrba
|
UTSW |
3 |
86202508 |
missense |
probably damaging |
1.00 |
R9236:Lrba
|
UTSW |
3 |
86261066 |
missense |
probably benign |
0.05 |
R9266:Lrba
|
UTSW |
3 |
86198774 |
missense |
probably benign |
0.08 |
R9297:Lrba
|
UTSW |
3 |
86280873 |
missense |
probably damaging |
1.00 |
R9404:Lrba
|
UTSW |
3 |
86205224 |
missense |
probably damaging |
0.99 |
R9617:Lrba
|
UTSW |
3 |
86267169 |
missense |
probably benign |
|
R9640:Lrba
|
UTSW |
3 |
86526875 |
nonsense |
probably null |
|
R9779:Lrba
|
UTSW |
3 |
86233078 |
missense |
probably damaging |
1.00 |
X0065:Lrba
|
UTSW |
3 |
86232396 |
missense |
possibly damaging |
0.95 |
X0065:Lrba
|
UTSW |
3 |
86205206 |
missense |
probably damaging |
1.00 |
Z1176:Lrba
|
UTSW |
3 |
86658839 |
missense |
possibly damaging |
0.85 |
Z1176:Lrba
|
UTSW |
3 |
86622845 |
missense |
probably benign |
0.31 |
Z1177:Lrba
|
UTSW |
3 |
86447356 |
missense |
probably null |
1.00 |
|
Mode of Inheritance |
Autosomal Recessive |
Local Stock | |
Repository | |
Last Updated |
2022-04-12 3:40 PM
by External Program
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Record Created |
2015-02-16 1:20 PM
by Emre Turer
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Record Posted |
2019-05-16 |
Phenotypic Description |
The oscar phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R1596, some of which showed susceptibility to dextran sodium sulfate (DSS)-induced colitis at 7 (Figure 1) and 10 days (Figure 2) after DSS exposure (1); weight loss is used to measure DSS susceptibility.
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Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 65 mutations. The DSS sensitivity phenotype was linked by continuous variable mapping to a mutation in Lrba: a C to T transition at base pair 86,350,304 (v38) on chromosome 3, or base pair 126,401 in the GenBank genomic region NC_000069 encoding Lrba. The strongest association was found with a recessive model of inheritance to the phenotype at day 7, wherein three variant homozygotes departed phenotypically from 16 homozygous reference mice and 11 heterozygous mice with a P value of 9.182 x 10-8 (Figure 3). The mutation corresponds to residue 4,159 in the mRNA sequence NM_030695 within exon 24 of 57 total exons.
4144 GATGCAGTAGACCAACAAAGGAGGGACTCCAGA
1287 -D--A--V--D--Q--Q--R--R--D--S--R-
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The mutated nucleotide is indicated in red. The mutation results in substitution of glutamine 1,292 for a premature stop codon (Q1292*) in the LRBA protein. The causative mutation in Lrba for the DSS sensitivity phenotype at day 7 and day 10 was validated by CRISPR-mediated knockout of the Lrba (Figure 4 (P = 3.908 x 10-8) and Figure 5 (P = 5.435 x 10-8), respectively).
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Illustration of Mutations in
Gene & Protein |
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Protein Prediction |
Lrba encodes lipopolysaccharide-responsive beige-like anchor protein (LRBA), a member of the WD (tryptophan/aspartic acid) repeat-like (WDL)-BEACH [beige and Chediak-Higashi syndrome]-WD (WBW) gene family. LRBA has similar features of both Lyst (alternatively, CHS/Beige; see the record for souris) and A-kinase anchor proteins (AKAPs). LRBA has a ConA-like domain, a VHS (VPS [vacuolar protein sorting]-27, Hrs [hepatocyte growth factor-regulated tyrosine kinase substrate], STAM [signal transducing adaptor molecule]) domain, a WDL domain, a DUF1088 (domain of unknown function 1088) domain, a pleckstrin homology (PH) domain, a BEACH domain with a SH3-binding site, and five WD40 domains (Figure 6) (2-4). The ConA-like domain putatively regulates protein trafficking and classification of proteins along the secretory pathway (5). VHS domains are often found near the N-termini of proteins that function in endocytosis or vesicular trafficking (SMART). The VHS domain putatively functions as an adaptor domain that assists in promoting the localization of proteins in the cell membrane or in membranes of the endocytic machinery. WDL motifs consist of approximately 40 amino acids, and putatively function as protein interaction motifs. WDL motifs share similar structures to WD40 repeats. WD40 motifs typically form β sheets arranged in a 7-bladed β propeller fold (6). WD40 motifs are protein interaction motifs that function in signaling, cell cycle control, and apoptosis. The DUF1088 domain is near the LRBA C-terminus (4). The DUF1088 domain is unique to LRBA and its paralog neurobeachin. PH domains interact with phosphatidylinositol within membranes as well as with G-proteins and protein kinase C. These interactions facilitate protein targeting to the correct cellular compartments and signaling pathway activation. The BEACH domain is a 280-amino acid region of unknown function (7). BEACH domains are found in several proteins that function in vesicle trafficking, maintaining membrane dynamics, and receptor signaling. The ConA-like and PH-BEACH domains interact with the cytoplasmic tail of cytotoxic T lymphocyte-associated protein-4 (CTLA-4); see the Background section for more information about the LRBA-CTLA-4 interaction (8). Mouse Lrba encodes three isoforms: alpha (9,903 base pair encoding 2,856 amino acids), beta (9,396 base pair encoding 2,792 amino acids), and gamma (8,854 base pair encoding 2,779 amino acids) (2). The three isoforms have identical 5’-ends, but differ at their 3’-termini. The alpha isoform has five WD repeats, the beta isoform has three, and the gamma isoform lacks WD repeats. All isoforms have a BEACH domain. The oscar mutation results in substitution of tyrosine 2,356 for a premature stop codon (Y2356*) in the LRBA protein; amino acid 2,356 is within the BEACH domain.
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Expression/Localization | LRBA is expressed in several tissues, including bone marrow, lymph nodes, spleen, fetal liver, placenta, kidney, and pancreas (9). LRBA expression is induced in B cells and macrophages by lipopolysaccharide (2). LRBA expression is increased in several types of cancers, including renal, pancreatic, colorectal lung, and central nervous system (10). LRBA localizes to the cytosol, Golgi apparatus, and some lysosomes (2).
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Background |
LRBA functions in the regulation of endosomal trafficking by mediating the endocytosis of ligand-activated receptors and immune effector molecules including CTLA-4 (Figure 7) (11). CLTA-4 is a receptor on activated T cells that regulates peripheral immune tolerance and homeostasis by inhibiting T cell activation (12). In unstimulated T cells CTLA-4 localizes to the Golgi apparatus, endosomes, secretory granules, and lysosomes. After T cell receptor stimulation, CTLA-4 traffics from vesicular compartments to the cell membrane. At the membrane, CTLA-4 is continuously endocytosed via clathrin-coated vesicles. Some endocytosed CTLA-4 are recycled to the cell membrane, while some are degraded by lysosomes (13). LRBA regulates recycling of CTLA-4 from endosomes to the cell membrane. Furthermore, LRBA putatively blocks trafficking of CTLA-4 to lysosomes and competes with AP-1 for CLTA-4 binding (8). LRBA also putatively functions in the vesicular trafficking of epidermal growth factor receptor (EGFR; see the record for Velvet) (10). EGFR signaling is activated by a variety of ligands and activates several signaling pathways leading to gene transcription, cell proliferation and cell migration. Ligand binding induces the formation of EGFR homo- or heterodimers and the activation of intrinsic receptor tyrosine kinase activity, resulting in trans-phosphorylation of cytoplasmic tyrosine residues. Trans-phosphorylation of receptor tyrosines creates binding sites for SH2 domain- and PTB domain-containing proteins which recruit complexes that propagate downstream signaling. Their binding leads to substrate phosphorylation and the activation of multiple pathways, including the Ras-MAPK, Src and Abl family kinase, JNK, STAT and PLC-γ pathways. These in turn regulate transcriptional programs controlling cell proliferation, death and differentiation, as well as signaling cascades controlling cell adhesion, motility and migration. Termination of signaling from the EGFR is mediated by receptor endocytosis (14;15). EGFR expression at the cell surface is regulated by clathrin-mediated endocytosis, resulting in either its lysosomal degradation or recycling to the cell surface (16). LRBA mutations result in reduced expression and phosphorylation of EGFR (10); however, it is unknown if LRBA and EGFR directly interact. Mutations in LRBA are linked to common variable immunodeficiency 8 with autoimmunity (CVID8; OMIM: #614700) (8;9;11;17;18). Patients with CVID8 have recurrent infections starting in early childhood and also can develop autoimmune disorders, including idiopathic thrombocytopenia purpura, autoimmune hemolytic anemia, and inflammatory bowel disease [(9); reviewed in (18;19)]. CVID8 patients can also have hypogammaglobulinemia, reduced numbers of switched memory B cells, and reduced numbers of CD4+ regulatory T cells (9;17). B cells from the patients showed a failure to proliferate, differentiate, or produce antibodies as well as an increased susceptibility to apoptosis (9). Mutations in LRBA are also linked to an autoimmune lymphoproliferative-like syndrome in which patients showed splenomegaly, lymphadenopathy, cytopenia, increased numbers of double-negative T cells, increased levels of Fas ligand (FasL; see the record for riogrande) in the serum, and impaired Fas (see the record for cherry)-mediated apoptosis (20). Mutations in LRBA are also linked to cases of autoimmunity (autoimmune lymphoproliferative syndrome) presenting as neonatal diabetes (21) as well as cases of early-onset chronic erosive polyarthritis (22). A homozygous LRBA mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) was identified in two siblings that exhibited infancy-onset type 1 diabetes, enteropathy, growth hormone deficiency, short stature, and immunodysregulation (18;23). An LRBA mutation (p.I2824P) that resulted in normal expression of the mutant protein was linked to early IBD-like symptoms; the patient did not exhibit overt immunodeficiency (24). Lrba-deficient (Lrba-/-) mice exhibited increased regulatory T cell numbers in the small intestine, increased myeloid-derived suppressor cell numbers in the spleen and mesenteric lymph nodes (25). Lrba-deficient mice exhibited reduced susceptibility to graft versus host disease challenge and impaired rejection of bone marrow grafts from mismatched donors as well as aberrant NK cell-mediated cytotoxicity (25). Lrba-/- mice showed progressive sensorineural hearing loss due to degermation of inner and outer hair cell stereociliary bundles (26). Lrba-/- mice showed normal responses to T-dependent and T-independent antigens as well as normal responses to acute infections with lymphocytic choriomeningitis virus or Salmonella typhimurium (27). The mice had normal levels of serum IgM and IgG, but had elevated serum and secretory basal IgA levels. The mice showed normal B and T cell development, B cell proliferation, B cell survival, isotype switching, and plasmablast differentiation. The mice showed reduced CTLA-4 expression in regulatory T cells and activated conventional CD4+ and CD8+ T cells, reduced peritoneal B-1a cell frequency, reduced IL-10 production, and increased percentages of T follicular helper cells in Peyer’s patches (27;28). The mice did not develop overt signs of autoimmunity. Lrba-/- mice showed compromised olfaction due to reduced concentrations of all three subunits (i.e., aolf, b1, and g13) of the olfactory heterotrimeric G protein (Golf) in the sensory cilia of olfactory neurons; the cilia morphology and the concentrations of other ciliary proteins were not changed (29).
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Putative Mechanism | Increased signaling from one or more of the endosomal TLRs (TLR3, TLR7, and TLR9) resulted in increased production of inflammatory cytokines and increased susceptibility to DSS-induced colitis in Lrba-/- mice (1). DSS-treated Lrba-/- mice showed increased infiltration of inflammatory cells in the colon as well as impaired epithelial cell architecture in the colon. The DSS-treated Lrba-/ colon showed increased expression levels of pro-inflammatory cytokines, including TNF, IL-6, IL-1-b, IFN-a, IFN-b, and IFN-g. T and B cells were not necessary for the development of DSS-induced colitis in the Lrba-/- mice. However, LRBA function in innate immune cells, namely macrophages and dendritic cells, was required for recovery and restoration of intestinal homeostasis after DSS treatment. Excessive type I interferon in the Lrba-/- mice did not contribute to DSS susceptibility. However, PI3K/AKT/mTOR signaling was increased in the Lrba-/- dendritic cells, resulting in hyperactivation of IRF3 and IRF7 in response to endosomal TLR stimulation and subsequent increased production of type I IFN, IFN-stimulated genes, and IRF-dependent cytokines.
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Primers |
PCR Primer
oscar_pcr_F: GGCGATGTCTCTAATAACATGGCCC
oscar_pcr_R: AAGCGCCATTGGAATACCTACCTTC
Sequencing Primer
oscar_seq_F: ACATGGCCCTATGCTAATTACTG
oscar_seq_R: GGGTTTGTAGTCCAGAAATTCCAC
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Genotyping | NOTE: These primers have not been validated. Primer ID: R15960017 Oscar genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition.
PCR Primers
Oscar (F): 5’- GGCGATGTCTCTAATAACATGGCCC-3’
Oscar (R): 5’- AAGCGCCATTGGAATACCTACCTTC-3’ Sequencing Primers
Oscar_seq(F): 5’- ACATGGCCCTATGCTAATTACTG-3’
Oscar_seq(R): 5’- GGGTTTGTAGTCCAGAAATTCCAC-3’
PCR program
1) 94°C 2:00
2) 94°C 0:30
3) 55°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 40X
6) 72°C 10:00
7) 4°C hold The following sequence of 711 nucleotides is amplified (Chr.3: 86350000-86350710, GRCm38; NCBI RefSeq: NC_000069): ggcgatgtct ctaataacat ggccctatgc taattactgt tgatttatgg tattagcatt
ataccatgat aactttgctt taaatttatg gtaagattag tcattgataa gtttctttta
attttacttt gtagtgtatt agaatttgaa tatttgttag atgcatttca gggaagttat
gaattctgtg ctgatgcctt cttttgaagt tcaacttact ttattagttc ttaacctttt
ctcttagata tcaaggcaac aggagcagac agcacaagga acagcaccag atgcagtaga
ccaacaaagg agggactcca gatccaccat gtttcgcatt cctgagttca agtggtctca
gatgcatcaa cgtctgctca ctgatctctt attttccata gaaacagata tacagatgtg
gagaaggttt gttcatatat tcactataga atacatgtat gaagcttagt ctttgttttc
aaagaaattt gtgtaaacat tttatattac cccaaacatt tgattgaaaa aaaagactat
aaattactct atgttagtat tctatcacat taccatttat cctccattct atgtgtggaa
tttctggact acaaacccag gaaaatccaa gatttcctgt actaaaaatt gctcgaggtt
tgttatagta tttatagaat tagctagaag gtaggtattc caatggcgct t FASTA sequence Primer binding sites are underlined and the sequencing primer is highlighted; the mutated C is shown in red text (C>T).
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References | 1. Wang, K., Zhan, W., McAlpine, W., Zhang, Z., Choi, J. H., Shi, H., Misawa, T., Yue, T., Zhang, D., Wang, Y., Ludwig, S., Russell, J., Tang, M., Li, X., Murray, A. R., Moresco, E. M. Y., Turer, E. E., and Beutler, B. (2019) Enhanced Susceptibility to Chemically Induced Colitis Caused by Excessive Endosomal TLR Signaling in LRBA-Deficient Mice. Proc Natl Acad Sci ,USA. May 2019, 201901407; DOI: 10.1073/pnas.1901407116. Accessed May 16, 2019.
3. Gebauer, D., Li, J., Jogl, G., Shen, Y., Myszka, D. G., and Tong, L. (2004) Crystal Structure of the PH-BEACH Domains of Human LRBA/BGL. Biochemistry. 43, 14873-14880.
6. Sondek, J., Bohm, A., Lambright, D. G., Hamm, H. E., and Sigler, P. B. (1996) Crystal Structure of a G-Protein Beta Gamma Dimer at 2.1A Resolution. Nature. 379, 369-374.
7. Nagle, D. L., Karim, M. A., Woolf, E. A., Holmgren, L., Bork, P., Misumi, D. J., McGrail, S. H., Dussault, B. J.,Jr, Perou, C. M., Boissy, R. E., Duyk, G. M., Spritz, R. A., and Moore, K. J. (1996) Identification and Mutation Analysis of the Complete Gene for Chediak-Higashi Syndrome. Nat Genet. 14, 307-311.
8. Lo, B., Zhang, K., Lu, W., Zheng, L., Zhang, Q., Kanellopoulou, C., Zhang, Y., Liu, Z., Fritz, J. M., Marsh, R., Husami, A., Kissell, D., Nortman, S., Chaturvedi, V., Haines, H., Young, L. R., Mo, J., Filipovich, A. H., Bleesing, J. J., Mustillo, P., Stephens, M., Rueda, C. M., Chougnet, C. A., Hoebe, K., McElwee, J., Hughes, J. D., Karakoc-Aydiner, E., Matthews, H. F., Price, S., Su, H. C., Rao, V. K., Lenardo, M. J., and Jordan, M. B. (2015) AUTOIMMUNE DISEASE. Patients with LRBA Deficiency show CTLA4 Loss and Immune Dysregulation Responsive to Abatacept Therapy. Science. 349, 436-440.
9. Lopez-Herrera, G., Tampella, G., Pan-Hammarstrom, Q., Herholz, P., Trujillo-Vargas, C. M., Phadwal, K., Simon, A. K., Moutschen, M., Etzioni, A., Mory, A., Srugo, I., Melamed, D., Hultenby, K., Liu, C., Baronio, M., Vitali, M., Philippet, P., Dideberg, V., Aghamohammadi, A., Rezaei, N., Enright, V., Du, L., Salzer, U., Eibel, H., Pfeifer, D., Veelken, H., Stauss, H., Lougaris, V., Plebani, A., Gertz, E. M., Schaffer, A. A., Hammarstrom, L., and Grimbacher, B. (2012) Deleterious Mutations in LRBA are Associated with a Syndrome of Immune Deficiency and Autoimmunity. Am J Hum Genet. 90, 986-1001.
10. Wang, J. W., Gamsby, J. J., Highfill, S. L., Mora, L. B., Bloom, G. C., Yeatman, T. J., Pan, T. C., Ramne, A. L., Chodosh, L. A., Cress, W. D., Chen, J., and Kerr, W. G. (2004) Deregulated Expression of LRBA Facilitates Cancer Cell Growth. Oncogene. 23, 4089-4097.
11. Alangari, A., Alsultan, A., Adly, N., Massaad, M. J., Kiani, I. S., Aljebreen, A., Raddaoui, E., Almomen, A. K., Al-Muhsen, S., Geha, R. S., and Alkuraya, F. S. (2012) LPS-Responsive Beige-Like Anchor (LRBA) Gene Mutation in a Family with Inflammatory Bowel Disease and Combined Immunodeficiency. J Allergy Clin Immunol. 130, 481-8.e2.
14. Das, M., and Fox, C. F. (1978) Molecular Mechanism of Mitogen Action: Processing of Receptor Induced by Epidermal Growth Factor. Proc Natl Acad Sci U S A. 75, 2644-2648.
15. Baulida, J., Kraus, M. H., Alimandi, M., Di Fiore, P. P., and Carpenter, G. (1996) All ErbB Receptors Other than the Epidermal Growth Factor Receptor are Endocytosis Impaired. J Biol Chem. 271, 5251-5257.
16. Sigismund, S., Argenzio, E., Tosoni, D., Cavallaro, E., Polo, S., and Di Fiore, P. P. (2008) Clathrin-Mediated Internalization is Essential for Sustained EGFR Signaling but Dispensable for Degradation. Dev Cell. 15, 209-219.
17. Charbonnier, L. M., Janssen, E., Chou, J., Ohsumi, T. K., Keles, S., Hsu, J. T., Massaad, M. J., Garcia-Lloret, M., Hanna-Wakim, R., Dbaibo, G., Alangari, A. A., Alsultan, A., Al-Zahrani, D., Geha, R. S., and Chatila, T. A. (2015) Regulatory T-Cell Deficiency and Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked-Like Disorder Caused by Loss-of-Function Mutations in LRBA. J Allergy Clin Immunol. 135, 217-227.
18. Habibi, S., Zaki-Dizaji, M., Rafiemanesh, H., Lo, B., Jamee, M., Gamez-Diaz, L., Salami, F., Kamali, A. N., Mohammadi, H., Abolhassani, H., Yazdani, R., Aghamohammadi, A., Anaya, J. M., and Azizi, G. (2019) Clinical, Immunologic, and Molecular Spectrum of Patients with LPS-Responsive Beige-Like Anchor Protein (LRBA) Deficiency: A Systematic Review. J Allergy Clin Immunol Pract. .
19. Alkhairy, O. K., Abolhassani, H., Rezaei, N., Fang, M., Andersen, K. K., Chavoshzadeh, Z., Mohammadzadeh, I., El-Rajab, M. A., Massaad, M., Chou, J., Aghamohammadi, A., Geha, R. S., and Hammarstrom, L. (2016) Spectrum of Phenotypes Associated with Mutations in LRBA. J Clin Immunol. 36, 33-45.
20. Revel-Vilk, S., Fischer, U., Keller, B., Nabhani, S., Gamez-Diaz, L., Rensing-Ehl, A., Gombert, M., Honscheid, A., Saleh, H., Shaag, A., Borkhardt, A., Grimbacher, B., Warnatz, K., Elpeleg, O., and Stepensky, P. (2015) Autoimmune Lymphoproliferative Syndrome-Like Disease in Patients with LRBA Mutation. Clin Immunol. 159, 84-92.
21. Johnson, M. B., De Franco, E., Lango Allen, H., Al Senani, A., Elbarbary, N., Siklar, Z., Berberoglu, M., Imane, Z., Haghighi, A., Razavi, Z., Ullah, I., Alyaarubi, S., Gardner, D., Ellard, S., Hattersley, A. T., and Flanagan, S. E. (2017) Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes. Diabetes. 66, 2316-2322.
22. Levy, E., Stolzenberg, M. C., Bruneau, J., Breton, S., Neven, B., Sauvion, S., Zarhrate, M., Nitschke, P., Fischer, A., Magerus-Chatinet, A., Quartier, P., and Rieux-Laucat, F. (2016) LRBA Deficiency with Autoimmunity and Early Onset Chronic Erosive Polyarthritis. Clin Immunol. 168, 88-93.
23. Schreiner, F., Plamper, M., Dueker, G., Schoenberger, S., Gamez-Diaz, L., Grimbacher, B., Hilger, A. C., Gohlke, B., Reutter, H., and Woelfle, J. (2016) Infancy-Onset T1DM, Short Stature, and Severe Immunodysregulation in Two Siblings with a Homozygous LRBA Mutation. J Clin Endocrinol Metab. 101, 898-904.
24. Serwas, N. K., Kansu, A., Santos-Valente, E., Kuloglu, Z., Demir, A., Yaman, A., Gamez Diaz, L. Y., Artan, R., Sayar, E., Ensari, A., Grimbacher, B., and Boztug, K. (2015) Atypical Manifestation of LRBA Deficiency with Predominant IBD-Like Phenotype. Inflamm Bowel Dis. 21, 40-47.
25. Park, M. Y., Sudan, R., Srivastava, N., Neelam, S., Youngs, C., Wang, J. W., Engelman, R. W., and Kerr, W. G. (2016) LRBA is Essential for Allogeneic Responses in Bone Marrow Transplantation. Sci Rep. 6, 36568.
26. Vogl, C., Butola, T., Haag, N., Hausrat, T. J., Leitner, M. G., Moutschen, M., Lefebvre, P. P., Speckmann, C., Garrett, L., Becker, L., Fuchs, H., Hrabe de Angelis, M., Nietzsche, S., Kessels, M. M., Oliver, D., Kneussel, M., Kilimann, M. W., and Strenzke, N. (2017) The BEACH Protein LRBA is Required for Hair Bundle Maintenance in Cochlear Hair Cells and for Hearing. EMBO Rep. 18, 2015-2029.
27. Gamez-Diaz, L., Neumann, J., Jager, F., Proietti, M., Felber, F., Soulas-Sprauel, P., Perruzza, L., Grassi, F., Kogl, T., Aichele, P., Kilimann, M., Grimbacher, B., and Jung, S. (2017) Immunological Phenotype of the Murine Lrba Knockout. Immunol Cell Biol. 95, 789-802.
28. Burnett, D. L., Parish, I. A., Masle-Farquhar, E., Brink, R., and Goodnow, C. C. (2017) Murine LRBA Deficiency Causes CTLA-4 Deficiency in Tregs without Progression to Immune Dysregulation. Immunol Cell Biol. 95, 775-788.
29. Kurtenbach, S., Giessl, A., Stromberg, S., Kremers, J., Atorf, J., Rasche, S., Neuhaus, E. M., Herve, D., Brandstatter, J. H., Asan, E., Hatt, H., and Kilimann, M. W. (2017) The BEACH Protein LRBA Promotes the Localization of the Heterotrimeric G-Protein Golf to Olfactory Cilia. Sci Rep. 7, 8409-017-08543-4.
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Science Writers | Anne Murray |
Illustrators | Diantha La Vine |
Authors | Emre Turer, William McAlpine, Noelle Hutchins, Jeff SoRelle, and Bruce Beutler |