Mutagenetix > Incidental Mutation

Incidental Mutation 'P0018:Robo2'

7661

Institutional Source

Beutler Lab

Gene Symbol

Robo2

Ensembl Gene

ENSMUSG00000052516

Gene Name

roundabout guidance receptor 2

Synonyms

2600013A04Rik, 9430089E08Rik, D230004I22Rik

MMRRC Submission

038271-MU

Accession Numbers

Essential gene?

Probably essential (E-score: 0.952) question?

Stock #

P0018 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

73688727-74208713 bp(-) (GRCm39)

Type of Mutation

missense

DNA Base Change (assembly)

T to C at 73843694 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Isoleucine to Valine at position 174 (I174V)

Ref Sequence

ENSEMBL: ENSMUSP00000113795 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000117200] [ENSMUST00000117785] [ENSMUST00000226478] [ENSMUST00000227347]

AlphaFold

no structure available at present

Predicted Effect

probably benign
Transcript: ENSMUST00000116586
AA Change: I174V

PolyPhen 2 Score 0.023 (Sensitivity: 0.95; Specificity: 0.81)

SMART Domains

Protein: ENSMUSP00000112285
Gene: ENSMUSG00000052516
AA Change: I174V

Domain	Start	End	E-Value	Type
signal peptide	1	21	N/A	INTRINSIC
IGc2	43	117	3.56e-9	SMART
IGc2	145	210	3.33e-9	SMART
IGc2	237	300	6.59e-13	SMART
IGc2	330	402	1.3e-11	SMART
IGc2	434	499	3.73e-12	SMART
FN3	526	608	1.42e-15	SMART
FN3	640	725	3.54e-2	SMART
FN3	740	827	6.15e-11	SMART
transmembrane domain	864	886	N/A	INTRINSIC
low complexity region	1044	1069	N/A	INTRINSIC
low complexity region	1076	1087	N/A	INTRINSIC

Predicted Effect

possibly damaging
Transcript: ENSMUST00000117200
AA Change: I174V

PolyPhen 2 Score 0.825 (Sensitivity: 0.84; Specificity: 0.93)

SMART Domains

Protein: ENSMUSP00000113795
Gene: ENSMUSG00000052516
AA Change: I174V

Domain	Start	End	E-Value	Type
signal peptide	1	21	N/A	INTRINSIC
IGc2	43	117	3.56e-9	SMART
IGc2	145	210	3.33e-9	SMART
IGc2	237	300	6.59e-13	SMART
IGc2	326	398	1.3e-11	SMART
IGc2	430	495	3.73e-12	SMART
FN3	522	604	1.42e-15	SMART
FN3	636	721	3.54e-2	SMART
FN3	736	823	6.15e-11	SMART
transmembrane domain	860	882	N/A	INTRINSIC
low complexity region	1040	1065	N/A	INTRINSIC
low complexity region	1072	1083	N/A	INTRINSIC
low complexity region	1191	1199	N/A	INTRINSIC
low complexity region	1210	1234	N/A	INTRINSIC
low complexity region	1318	1342	N/A	INTRINSIC

Predicted Effect

probably benign
Transcript: ENSMUST00000117785
AA Change: I174V

PolyPhen 2 Score 0.046 (Sensitivity: 0.94; Specificity: 0.83)

SMART Domains

Protein: ENSMUSP00000112776
Gene: ENSMUSG00000052516
AA Change: I174V

Domain	Start	End	E-Value	Type
signal peptide	1	21	N/A	INTRINSIC
IGc2	43	117	3.56e-9	SMART
IGc2	145	210	3.33e-9	SMART
IGc2	237	300	6.59e-13	SMART
IGc2	326	398	1.3e-11	SMART
IGc2	430	495	3.73e-12	SMART
FN3	522	604	1.42e-15	SMART
FN3	636	721	3.54e-2	SMART
FN3	736	823	6.15e-11	SMART
transmembrane domain	860	882	N/A	INTRINSIC
low complexity region	1072	1107	N/A	INTRINSIC
low complexity region	1114	1125	N/A	INTRINSIC
low complexity region	1233	1241	N/A	INTRINSIC
low complexity region	1252	1276	N/A	INTRINSIC
low complexity region	1351	1362	N/A	INTRINSIC
low complexity region	1451	1475	N/A	INTRINSIC

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000140062

Predicted Effect

probably benign
Transcript: ENSMUST00000226478
AA Change: I174V

PolyPhen 2 Score 0.157 (Sensitivity: 0.92; Specificity: 0.87)

Predicted Effect

probably benign
Transcript: ENSMUST00000227347
AA Change: I174V

PolyPhen 2 Score 0.063 (Sensitivity: 0.94; Specificity: 0.84)

Meta Mutation Damage Score

0.0741

Coding Region Coverage

1x: 83.8%
3x: 77.4%
10x: 57.9%
20x: 38.3%

Validation Efficiency

72% (76/106)

MGI Phenotype

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the ROBO family, part of the immunoglobulin superfamily of proteins that are highly conserved from fly to human. The encoded protein is a transmembrane receptor for the slit homolog 2 protein and functions in axon guidance and cell migration. Mutations in this gene are associated with vesicoureteral reflux, characterized by the backward flow of urine from the bladder into the ureters or the kidney. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
PHENOTYPE: Homozygous mutants display postnatal lethality, abnormal ureteric bud development, multiple fused kidneys, multiple ureters, and abnormal commissural axon growth. [provided by MGI curators]

Allele List at MGI

All alleles(6) : Targeted(3) Gene trapped(3)

Other mutations in this stock

Total: 14 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
AAdacl4fm3	A	T	4: 144,429,767 (GRCm39)	D407E	probably benign	Het
Brip1	C	T	11: 85,999,694 (GRCm39)	V763I	possibly damaging	Het
Cspg4b	A	G	13: 113,504,040 (GRCm39)	D1723G	possibly damaging	Het
Cxxc1	C	T	18: 74,353,992 (GRCm39)	R593C	probably damaging	Het
Erbb4	T	A	1: 68,110,835 (GRCm39)	M993L	probably benign	Het
Ftsj3	C	A	11: 106,145,634 (GRCm39)	M66I	possibly damaging	Het
Galnt2	T	A	8: 125,063,350 (GRCm39)	Y357N	probably damaging	Het
Hgsnat	C	T	8: 26,458,382 (GRCm39)		probably benign	Het
Katna1	A	T	10: 7,617,223 (GRCm39)	T72S	probably damaging	Het
Nell1	A	G	7: 49,770,439 (GRCm39)	D166G	probably damaging	Het
Nlgn1	G	T	3: 25,490,741 (GRCm39)	P329T	probably damaging	Het
Pclo	A	T	5: 14,727,735 (GRCm39)		probably benign	Het
Sufu	A	G	19: 46,463,933 (GRCm39)		probably benign	Het
Tmub1	C	A	5: 24,651,755 (GRCm39)	A55S	possibly damaging	Het

Other mutations in Robo2

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL00666:Robo2	APN	16	73,758,588 (GRCm39)	missense	probably benign
IGL00849:Robo2	APN	16	73,770,665 (GRCm39)	missense	possibly damaging	0.80
IGL00908:Robo2	APN	16	73,782,579 (GRCm39)	missense	probably damaging	0.98
IGL00944:Robo2	APN	16	73,730,585 (GRCm39)	missense	possibly damaging	0.92
IGL00955:Robo2	APN	16	73,812,860 (GRCm39)	missense	probably damaging	1.00
IGL00970:Robo2	APN	16	73,693,934 (GRCm39)	missense	probably benign	0.00
IGL01020:Robo2	APN	16	73,725,039 (GRCm39)	missense	probably benign	0.06
IGL01347:Robo2	APN	16	74,149,744 (GRCm39)	missense	probably damaging	1.00
IGL02280:Robo2	APN	16	73,843,704 (GRCm39)	missense	probably damaging	1.00
IGL02424:Robo2	APN	16	73,770,189 (GRCm39)	missense	possibly damaging	0.89
IGL03376:Robo2	APN	16	73,753,380 (GRCm39)	missense	probably damaging	1.00
LCD18:Robo2	UTSW	16	74,055,954 (GRCm38)	intron	probably benign
R0314:Robo2	UTSW	16	73,753,525 (GRCm39)	missense	probably damaging	1.00
R0324:Robo2	UTSW	16	73,764,739 (GRCm39)	missense	probably damaging	1.00
R0539:Robo2	UTSW	16	73,782,462 (GRCm39)	splice site	probably benign
R0620:Robo2	UTSW	16	73,764,690 (GRCm39)	missense	possibly damaging	0.92
R0630:Robo2	UTSW	16	73,713,093 (GRCm39)	missense	probably benign	0.05
R0701:Robo2	UTSW	16	73,843,762 (GRCm39)	missense	probably damaging	1.00
R1155:Robo2	UTSW	16	73,831,996 (GRCm39)	missense	probably damaging	1.00
R1168:Robo2	UTSW	16	73,745,184 (GRCm39)	missense	probably damaging	1.00
R1195:Robo2	UTSW	16	73,713,016 (GRCm39)	splice site	probably null
R1195:Robo2	UTSW	16	73,713,016 (GRCm39)	splice site	probably null
R1195:Robo2	UTSW	16	73,713,016 (GRCm39)	splice site	probably null
R1317:Robo2	UTSW	16	73,831,912 (GRCm39)	missense	probably damaging	1.00
R1422:Robo2	UTSW	16	73,775,336 (GRCm39)	missense	probably damaging	0.99
R1452:Robo2	UTSW	16	73,758,798 (GRCm39)	missense	probably damaging	1.00
R1649:Robo2	UTSW	16	73,695,889 (GRCm39)	missense	probably benign	0.36
R1709:Robo2	UTSW	16	73,753,411 (GRCm39)	missense	possibly damaging	0.83
R1751:Robo2	UTSW	16	73,831,912 (GRCm39)	missense	probably damaging	1.00
R1761:Robo2	UTSW	16	73,831,912 (GRCm39)	missense	probably damaging	1.00
R1885:Robo2	UTSW	16	73,713,033 (GRCm39)	missense	probably benign	0.00
R1911:Robo2	UTSW	16	73,755,213 (GRCm39)	missense	probably damaging	1.00
R1919:Robo2	UTSW	16	73,696,042 (GRCm39)	missense	probably benign
R2005:Robo2	UTSW	16	73,730,003 (GRCm39)	missense	possibly damaging	0.82
R2851:Robo2	UTSW	16	73,758,776 (GRCm39)	missense	probably damaging	1.00
R3732:Robo2	UTSW	16	73,717,635 (GRCm39)	missense	possibly damaging	0.64
R3732:Robo2	UTSW	16	73,717,635 (GRCm39)	missense	possibly damaging	0.64
R3733:Robo2	UTSW	16	73,717,635 (GRCm39)	missense	possibly damaging	0.64
R3734:Robo2	UTSW	16	73,717,635 (GRCm39)	missense	possibly damaging	0.64
R3913:Robo2	UTSW	16	73,831,893 (GRCm39)	missense	probably damaging	1.00
R3956:Robo2	UTSW	16	73,758,755 (GRCm39)	missense	probably damaging	1.00
R4394:Robo2	UTSW	16	73,745,267 (GRCm39)	missense	probably benign	0.13
R4426:Robo2	UTSW	16	73,745,154 (GRCm39)	missense	probably damaging	1.00
R4437:Robo2	UTSW	16	73,770,132 (GRCm39)	missense	possibly damaging	0.88
R4454:Robo2	UTSW	16	74,149,407 (GRCm39)	intron	probably benign
R4478:Robo2	UTSW	16	73,812,761 (GRCm39)	missense	probably damaging	1.00
R4586:Robo2	UTSW	16	73,758,761 (GRCm39)	missense	probably damaging	0.96
R4621:Robo2	UTSW	16	73,782,821 (GRCm39)	missense	probably benign	0.00
R4673:Robo2	UTSW	16	73,701,266 (GRCm39)	splice site	probably null
R4798:Robo2	UTSW	16	74,149,633 (GRCm39)	missense	probably damaging	1.00
R4812:Robo2	UTSW	16	73,713,176 (GRCm39)	missense	probably benign	0.00
R4855:Robo2	UTSW	16	73,768,079 (GRCm39)	missense	probably damaging	1.00
R4910:Robo2	UTSW	16	73,730,666 (GRCm39)	missense	probably damaging	0.99
R4916:Robo2	UTSW	16	73,695,803 (GRCm39)	missense	possibly damaging	0.53
R4948:Robo2	UTSW	16	74,149,726 (GRCm39)	missense	possibly damaging	0.88
R5325:Robo2	UTSW	16	73,770,673 (GRCm39)	missense	possibly damaging	0.72
R5326:Robo2	UTSW	16	73,695,853 (GRCm39)	missense	probably benign	0.20
R5447:Robo2	UTSW	16	73,770,654 (GRCm39)	nonsense	probably null
R5542:Robo2	UTSW	16	73,695,853 (GRCm39)	missense	probably benign	0.20
R5545:Robo2	UTSW	16	73,758,635 (GRCm39)	missense	probably damaging	1.00
R5646:Robo2	UTSW	16	73,758,707 (GRCm39)	missense	probably damaging	0.99
R5734:Robo2	UTSW	16	74,149,672 (GRCm39)	missense	probably damaging	1.00
R5892:Robo2	UTSW	16	73,692,668 (GRCm39)	utr 3 prime	probably benign
R5960:Robo2	UTSW	16	73,730,603 (GRCm39)	missense	probably damaging	1.00
R6126:Robo2	UTSW	16	73,717,570 (GRCm39)	missense	probably benign	0.00
R6130:Robo2	UTSW	16	73,717,570 (GRCm39)	missense	probably benign	0.00
R6153:Robo2	UTSW	16	73,717,617 (GRCm39)	missense	probably damaging	1.00
R6240:Robo2	UTSW	16	73,779,027 (GRCm39)	missense	probably damaging	1.00
R6247:Robo2	UTSW	16	73,764,672 (GRCm39)	missense	probably damaging	1.00
R6304:Robo2	UTSW	16	73,755,196 (GRCm39)	missense	probably damaging	1.00
R6337:Robo2	UTSW	16	73,725,039 (GRCm39)	missense	probably benign	0.06
R6431:Robo2	UTSW	16	73,843,697 (GRCm39)	nonsense	probably null
R6440:Robo2	UTSW	16	73,713,010 (GRCm39)	missense	probably benign	0.31
R6596:Robo2	UTSW	16	73,767,996 (GRCm39)	missense	probably damaging	1.00
R6919:Robo2	UTSW	16	73,758,755 (GRCm39)	missense	probably damaging	1.00
R6927:Robo2	UTSW	16	73,778,946 (GRCm39)	missense	probably damaging	1.00
R7029:Robo2	UTSW	16	73,745,225 (GRCm39)	missense	probably damaging	1.00
R7078:Robo2	UTSW	16	74,149,504 (GRCm39)	missense	probably damaging	1.00
R7092:Robo2	UTSW	16	73,753,531 (GRCm39)	missense	probably damaging	0.99
R7136:Robo2	UTSW	16	73,753,438 (GRCm39)	missense	probably damaging	0.99
R7192:Robo2	UTSW	16	73,717,638 (GRCm39)	missense	probably benign	0.19
R7569:Robo2	UTSW	16	73,832,003 (GRCm39)	missense	possibly damaging	0.82
R7686:Robo2	UTSW	16	73,755,293 (GRCm39)	missense	probably damaging	1.00
R7720:Robo2	UTSW	16	73,693,903 (GRCm39)	missense	probably benign	0.00
R7772:Robo2	UTSW	16	73,758,777 (GRCm39)	missense	probably benign	0.24
R7822:Robo2	UTSW	16	73,770,059 (GRCm39)	missense	probably damaging	1.00
R7849:Robo2	UTSW	16	73,770,132 (GRCm39)	missense	possibly damaging	0.88
R7881:Robo2	UTSW	16	73,717,585 (GRCm39)	missense	probably benign	0.00
R7897:Robo2	UTSW	16	73,695,838 (GRCm39)	missense	probably benign
R8135:Robo2	UTSW	16	73,730,048 (GRCm39)	missense	probably benign	0.04
R8297:Robo2	UTSW	16	73,812,814 (GRCm39)	nonsense	probably null
R8307:Robo2	UTSW	16	73,753,498 (GRCm39)	missense	probably damaging	1.00
R8379:Robo2	UTSW	16	73,730,588 (GRCm39)	missense	probably damaging	0.99
R8393:Robo2	UTSW	16	73,775,382 (GRCm39)	missense	probably damaging	1.00
R8474:Robo2	UTSW	16	73,745,150 (GRCm39)	missense	probably damaging	1.00
R8500:Robo2	UTSW	16	73,745,228 (GRCm39)	missense	probably damaging	1.00
R8721:Robo2	UTSW	16	73,703,798 (GRCm39)	missense
R8734:Robo2	UTSW	16	73,764,651 (GRCm39)	splice site	probably benign
R8735:Robo2	UTSW	16	73,755,247 (GRCm39)	missense	probably damaging	1.00
R8840:Robo2	UTSW	16	73,782,570 (GRCm39)	missense	probably damaging	1.00
R8937:Robo2	UTSW	16	73,770,150 (GRCm39)	missense	probably damaging	1.00
R8937:Robo2	UTSW	16	73,770,149 (GRCm39)	missense	probably damaging	1.00
R8968:Robo2	UTSW	16	73,767,941 (GRCm39)	critical splice donor site	probably null
R9134:Robo2	UTSW	16	73,703,738 (GRCm39)	missense
R9622:Robo2	UTSW	16	73,729,952 (GRCm39)	missense	probably benign	0.02
R9662:Robo2	UTSW	16	73,758,566 (GRCm39)	critical splice donor site	probably null
R9708:Robo2	UTSW	16	73,770,197 (GRCm39)	missense	possibly damaging	0.70
R9779:Robo2	UTSW	16	73,767,965 (GRCm39)	missense	probably damaging	0.97
X0063:Robo2	UTSW	16	73,842,716 (GRCm39)	missense	probably damaging	1.00
Z1176:Robo2	UTSW	16	73,730,479 (GRCm39)	missense	probably benign	0.35
Z1177:Robo2	UTSW	16	73,737,187 (GRCm39)	critical splice acceptor site	probably null

Protein Function and Prediction

Robo2 is a member of the Roundabout (Robo) family of immunoglobulin superfamily proteins that function as axon guidance and neuronal migration receptors (1;2). In Drosophila, robo functions to control the decision by axons to cross the central nervous system midline (2). It has been proposed that Robo2 signaling is a negative regulator on nephrin signaling to influence podocyte foot process architecture (3).

Expression/Localization

RT-PCR ELISA detected highest expression of ROBO2 in adult and fetal brain, adult ovary, and in most individual brain regions examined. Intermediate expression was detected in fetal liver and in adult lung, kidney, spleen, testis, and spinal cord (4). Little to no expression was detected in adult pancreas, heart, liver, and skeletal muscle (4). Other researchers identified two splice variants of ROBO2, ROBO2a and ROBO2b (5). RT-PCR detected ROBO2b expression in all tissues examined except skeletal muscle (5). ROBO2a showed a more restricted expression pattern, with highest expression in fetal brain and significantly lower levels in adult brain, kidney, spleen, testis, and spinal cord (5). Both isoforms were detected in human fetal brain at all developmental stages examined (5). In the kidney, Robo2 is expressed at the basal surface of mouse podocytes and colocalizes with nephrin (3).

Background

Mutations in ROBO2 cause vesicoureteral reflux 2 (OMIM: # 610878), a condition that is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys, and is a risk factor for urinary tract infections (6).

Robo2^{tm1.1Rilm/tm1.1Rilm}; MGI:3759448

involves: 129

Homozygous mice die at birth. Examination of embryos determined that the mice have abnormal brain interneuron morphology as well as abnormal neurite morphology (7).

Robo2^{tm1.1Rilm/tm1.1Rilm}; MGI:3759448

involves: 129 * C57BL/6 * FVB/N

Homozygous animals die shortly after birth and have multiplex, dysplastic kidneys with cysts and a short ureter (6).

Robo2^{tm1Mrt/tm1Mrt}; MGI:3043127

involves: 129P2/OlaHsd * 129/Sv * C57BL/6 * CD-1

Similar to the other mouse models, homozygous mice fail to survive after birth and have an abnormal ureter morphology (8).

Robo2^{tm1Mrt/tm1Mrt}; MGI:3043127

Not Specified

Homozygous animals have abnormal axon guidance and abnormal spinal cord lateral column morphology (9).

References

1. Fricke, C., Lee, J. S., Geiger-Rudolph, S., Bonhoeffer, F., and Chien, C. B. (2001) Astray, a Zebrafish Roundabout Homolog Required for Retinal Axon Guidance. Science. 292, 507-510.

2. Kidd, T., Brose, K., Mitchell, K. J., Fetter, R. D., Tessier-Lavigne, M., Goodman, C. S., and Tear, G. (1998) Roundabout Controls Axon Crossing of the CNS Midline and Defines a Novel Subfamily of Evolutionarily Conserved Guidance Receptors. Cell. 92, 205-215.