Mutagenetix > Incidental Mutation

Incidental Mutation 'R0071:Folr1'

17002

Institutional Source

Beutler Lab

Gene Symbol

Folr1

Ensembl Gene

ENSMUSG00000001827

Gene Name

folate receptor alpha

Synonyms

folate receptor [a], Folbp1, FBP1, folate-binding protein 1, Folbp-1

MMRRC Submission

038362-MU

Accession Numbers

Essential gene?

Essential (E-score: 1.000) question?

Stock #

R0071 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

101507551-101519974 bp(-) (GRCm39)

Type of Mutation

critical splice donor site (2 bp from exon)

DNA Base Change (assembly)

A to G at 101513130 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Ref Sequence

ENSEMBL: ENSMUSP00000115077 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000106981] [ENSMUST00000106982] [ENSMUST00000106983] [ENSMUST00000106985] [ENSMUST00000106986] [ENSMUST00000123321] [ENSMUST00000126204] [ENSMUST00000134145] [ENSMUST00000140068] [ENSMUST00000151706] [ENSMUST00000123630] [ENSMUST00000209334] [ENSMUST00000155311] [ENSMUST00000150184] [ENSMUST00000124026] [ENSMUST00000140584]

AlphaFold

P35846

Predicted Effect

probably null
Transcript: ENSMUST00000001882

SMART Domains

Protein: ENSMUSP00000001882
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
Pfam:Folate_rec	34	209	2.4e-61	PFAM
low complexity region	242	251	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000106981

SMART Domains

Protein: ENSMUSP00000102594
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
Pfam:Folate_rec	34	209	2.4e-61	PFAM
low complexity region	242	251	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000106982

SMART Domains

Protein: ENSMUSP00000102595
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
Pfam:Folate_rec	34	209	2.4e-61	PFAM
low complexity region	242	251	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000106983

SMART Domains

Protein: ENSMUSP00000102596
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
Pfam:Folate_rec	34	209	4.2e-68	PFAM
low complexity region	242	251	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000106985

SMART Domains

Protein: ENSMUSP00000102598
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
Pfam:Folate_rec	34	209	2.4e-61	PFAM
low complexity region	242	251	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000106986

SMART Domains

Protein: ENSMUSP00000102599
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
Pfam:Folate_rec	34	209	2.4e-61	PFAM
low complexity region	242	251	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000123321

SMART Domains

Protein: ENSMUSP00000114167
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
PDB:4LRH\|H	21	54	6e-13	PDB

Predicted Effect

probably null
Transcript: ENSMUST00000126204

SMART Domains

Protein: ENSMUSP00000117175
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
Pfam:Folate_rec	34	137	2.9e-38	PFAM

Predicted Effect

probably null
Transcript: ENSMUST00000134145

SMART Domains

Protein: ENSMUSP00000118547
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
Pfam:Folate_rec	34	104	2.6e-25	PFAM

Predicted Effect

probably null
Transcript: ENSMUST00000140068

SMART Domains

Protein: ENSMUSP00000114633
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
Pfam:Folate_rec	34	160	9.5e-47	PFAM

Predicted Effect

probably null
Transcript: ENSMUST00000151706

SMART Domains

Protein: ENSMUSP00000115077
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
Pfam:Folate_rec	34	157	8.9e-47	PFAM

Predicted Effect

silent
Transcript: ENSMUST00000123630

SMART Domains

Protein: ENSMUSP00000121947
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
PDB:4LRH\|H	21	54	4e-13	PDB

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000125298

Predicted Effect

probably benign
Transcript: ENSMUST00000209334

Predicted Effect

probably benign
Transcript: ENSMUST00000155311

SMART Domains

Protein: ENSMUSP00000115360
Gene: ENSMUSG00000001827

Domain	Start	End	E-Value	Type
signal peptide	1	19	N/A	INTRINSIC
PDB:4LRH\|H	21	53	3e-12	PDB

Predicted Effect

probably benign
Transcript: ENSMUST00000150184

Predicted Effect

probably benign
Transcript: ENSMUST00000124026

Predicted Effect

probably benign
Transcript: ENSMUST00000140584

Meta Mutation Damage Score

0.9488

Coding Region Coverage

1x: 88.2%
3x: 84.4%
10x: 70.8%
20x: 43.5%

Validation Efficiency

93% (94/101)

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 folate receptor family. Members of this gene family bind folic acid and its reduced derivatives, and transport 5-methyltetrahydrofolate into cells. This gene product is a secreted protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form. Mutations in this gene have been associated with neurodegeneration due to cerebral folate transport deficiency. Due to the presence of two promoters, multiple transcription start sites, and alternative splicing, multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2009]
PHENOTYPE: Embryos homozygous for a knock-out allele are growth retarded and malformed, show multiple developmental anomalies, including neural and craniofacial defects, and die by E10. Folate supplementation of pregnant dams reduces embryonic mortality and improves many of the adverse developmental effects. [provided by MGI curators]

Allele List at MGI

All alleles(359) : Targeted(3) Gene trapped(356)

Other mutations in this stock

Total: 51 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
Acrbp	T	C	6: 125,027,915 (GRCm39)		probably benign	Het
Amotl1	G	A	9: 14,460,069 (GRCm39)	A890V	probably benign	Het
Aox3	T	A	1: 58,211,050 (GRCm39)	C931*	probably null	Het
Apob	T	A	12: 8,052,111 (GRCm39)	V1184E	probably damaging	Het
Bbx	C	T	16: 50,100,755 (GRCm39)	E47K	probably benign	Het
Bccip	A	G	7: 133,315,960 (GRCm39)	D72G	probably damaging	Het
Bckdha	A	T	7: 25,329,868 (GRCm39)		probably null	Het
Bmerb1	A	G	16: 13,906,818 (GRCm39)	D11G	probably damaging	Het
Cald1	C	T	6: 34,735,069 (GRCm39)		probably benign	Het
Cdk11b	T	C	4: 155,733,880 (GRCm39)		probably benign	Het
Cebpe	G	T	14: 54,948,061 (GRCm39)	R261S	probably damaging	Het
Cep95	C	T	11: 106,681,554 (GRCm39)		probably benign	Het
Chi3l1	T	C	1: 134,113,017 (GRCm39)	Y150H	probably benign	Het
Chrnd	T	C	1: 87,120,559 (GRCm39)		probably benign	Het
Cog2	T	C	8: 125,275,407 (GRCm39)		probably benign	Het
Coro7	A	T	16: 4,488,391 (GRCm39)	L93Q	probably damaging	Het
Csmd3	T	C	15: 47,460,217 (GRCm39)	T3525A	probably benign	Het
Fam227b	T	A	2: 125,965,994 (GRCm39)	N144Y	probably benign	Het
Fhod1	A	T	8: 106,063,857 (GRCm39)		probably null	Het
Glis3	C	T	19: 28,241,255 (GRCm39)		probably benign	Het
Golgb1	G	A	16: 36,735,865 (GRCm39)	R1704Q	probably benign	Het
Helz2	T	C	2: 180,878,200 (GRCm39)	Y866C	probably damaging	Het
Kcnma1	C	T	14: 23,576,835 (GRCm39)	R236H	probably damaging	Het
Lct	C	T	1: 128,219,755 (GRCm39)	W1631*	probably null	Het
Limk1	G	T	5: 134,690,245 (GRCm39)	Q104K	probably benign	Het
Ly75	T	C	2: 60,152,163 (GRCm39)	K1130R	probably benign	Het
Mdm1	A	G	10: 117,982,701 (GRCm39)	E112G	probably damaging	Het
Myo7a	A	T	7: 97,706,037 (GRCm39)	Y1836N	probably damaging	Het
Nsun7	A	G	5: 66,421,388 (GRCm39)	Y118C	probably benign	Het
Or13a20	A	T	7: 140,232,170 (GRCm39)	I93F	probably benign	Het
Or2d36	A	G	7: 106,746,919 (GRCm39)	Y132C	probably damaging	Het
Osbpl11	T	C	16: 33,034,708 (GRCm39)		probably benign	Het
Pik3cb	A	T	9: 98,926,918 (GRCm39)	D886E	probably benign	Het
Pkhd1	T	A	1: 20,271,568 (GRCm39)	Y2995F	probably benign	Het
Raver2	C	T	4: 100,977,642 (GRCm39)		probably benign	Het
Sec22c	A	G	9: 121,521,979 (GRCm39)	F44L	probably damaging	Het
Sephs1	A	G	2: 4,904,371 (GRCm39)	T250A	probably benign	Het
Shoc1	A	G	4: 59,059,643 (GRCm39)	Y1006H	possibly damaging	Het
Sobp	A	G	10: 43,033,993 (GRCm39)	L111P	probably damaging	Het
Sparcl1	G	T	5: 104,233,707 (GRCm39)	Y547*	probably null	Het
Spata31d1b	G	A	13: 59,863,163 (GRCm39)	A104T	probably benign	Het
Spsb3	A	G	17: 25,106,878 (GRCm39)	D184G	probably damaging	Het
Sptan1	A	T	2: 29,893,354 (GRCm39)	K1148*	probably null	Het
Tdrd12	A	G	7: 35,228,671 (GRCm39)	V17A	possibly damaging	Het
Tlr9	A	G	9: 106,100,777 (GRCm39)	T23A	probably benign	Het
Tra2b	A	T	16: 22,073,151 (GRCm39)		probably benign	Het
Tspan15	A	G	10: 62,038,849 (GRCm39)		probably benign	Het
Ttc41	A	G	10: 86,572,710 (GRCm39)	N694S	probably benign	Het
Ube3b	G	A	5: 114,557,558 (GRCm39)	G1014D	probably damaging	Het
Unc5d	A	G	8: 29,209,854 (GRCm39)	V422A	possibly damaging	Het
Vmn2r80	C	T	10: 79,007,566 (GRCm39)	T514I	possibly damaging	Het

Other mutations in Folr1

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL01916:Folr1	APN	7	101,507,947 (GRCm39)	missense	probably benign	0.00
IGL02423:Folr1	APN	7	101,507,732 (GRCm39)	missense	probably benign	0.00
R0071:Folr1	UTSW	7	101,513,130 (GRCm39)	critical splice donor site	probably null
R1022:Folr1	UTSW	7	101,507,810 (GRCm39)	missense	probably damaging	0.98
R1024:Folr1	UTSW	7	101,507,810 (GRCm39)	missense	probably damaging	0.98
R1562:Folr1	UTSW	7	101,507,801 (GRCm39)	missense	probably damaging	0.98
R2299:Folr1	UTSW	7	101,513,199 (GRCm39)	missense	probably damaging	1.00
R3690:Folr1	UTSW	7	101,507,745 (GRCm39)	missense	probably benign	0.06
R4746:Folr1	UTSW	7	101,513,184 (GRCm39)	missense	probably damaging	1.00
R4747:Folr1	UTSW	7	101,513,184 (GRCm39)	missense	probably damaging	1.00
R5319:Folr1	UTSW	7	101,513,184 (GRCm39)	missense	probably damaging	1.00
R6243:Folr1	UTSW	7	101,513,172 (GRCm39)	missense	probably damaging	1.00
R6275:Folr1	UTSW	7	101,508,742 (GRCm39)	missense	probably damaging	0.99
R7284:Folr1	UTSW	7	101,508,677 (GRCm39)	missense	possibly damaging	0.67

Protein Function and Prediction

Folr1 encodes the GPI-anchored folate receptor [alternatively, folate-binding protein (FBP)] (1). FOLR1 binds with high affinity to folic acid and other folic acid derivatives to mediate the delivery of 5’methyltetrahydrofolate to the interior of cells. Steinfeld et al. found that FOLR1 is the major human folate transporter across the blood-brain barrier and is essential for cerebral folate supply (2). Studies have shown that FOLR1 is critical for embryonic development (3). Disruption of both Folr1 alleles in mice leads to malformations and embryonic lethality at the time of neural tube closure (3). Studies have shown that, in response to folic acid, FOLR1 translocates to the nucleus and acts as a transcription factor (4). FOLR1 binds to Hes1 and Fgfr4, indicating that FOLR1 is involved in stem cell maintenance and skeletal muscle differentiation, respectively (4). Other putative Folr1 targets indicate that FOLR1 may also regulate developmental genes involved in myogenesis, skeletonogenesis, cell mobility, neural crest cell migration, cranial and cardiac neural crest formation, hair morphogenesis, oligodendrogenesis, spermatogenesis, melanogenesis, and epithelial to mesenchymal transformation (4). FOLR1 has been identified as a tumor antigen/biomarker (5).

Expression/Localization

Northern blot analysis revealed a 1.1-kb FOLR1 mRNA in human KB cells, placenta, thymic epithelium, and brain, but not in liver (6). Real-time PCR of human tissues detected significant FOLR1 expression in the kidney (2). Membrane-bound and soluble forms of FOLR1 have been found in kidney, placenta, serum, milk, and in several cell lines.

Background

Mutations in FOLR1 are linked to neurodegeneration due to cerebral folate transport deficiency [OMIM: 613068; (2;7)].

Folr1^{tm1Fnn/tm1Fnn}; MGI: 2383986

involves: 129 * C57BL/6J

Homozygotes have a decreased level of folate in the plasma and colonic mucosa (8).

Folr1^{tm1Fnn/tm1Fnn}; MGI: 2383986

involves: 129P2/OlaHsd * C57BL/6J

Embryos homozygous for a knock-out allele are growth retarded and malformed, show multiple developmental anomalies, including neural and craniofacial defects, and die by E10. Folate supplementation of pregnant dams reduces embryonic mortality and improves many of the adverse developmental effects (3).

References

1. Ratnam, M., Marquardt, H., Duhring, J. L., and Freisheim, J. H. (1989) Homologous Membrane Folate Binding Proteins in Human Placenta: Cloning and Sequence of a cDNA. Biochemistry. 28, 8249-8254.

2. Steinfeld, R., Grapp, M., Kraetzner, R., Dreha-Kulaczewski, S., Helms, G., Dechent, P., Wevers, R., Grosso, S., and Gartner, J. (2009) Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency: A Treatable Neurodegenerative Disorder Associated with Disturbed Myelin Metabolism. Am J Hum Genet. 85, 354-363.

3. Piedrahita, J. A., Oetama, B., Bennett, G. D., van Waes, J., Kamen, B. A., Richardson, J., Lacey, S. W., Anderson, R. G., and Finnell, R. H. (1999) Mice Lacking the Folic Acid-Binding Protein Folbp1 are Defective in Early Embryonic Development. Nat Genet. 23, 228-232.

4. Boshnjaku, V., Shim, K. W., Tsurubuchi, T., Ichi, S., Szany, E. V., Xi, G., Mania-Farnell, B., McLone, D. G., Tomita, T., and Mayanil, C. S. (2012) Nuclear Localization of Folate Receptor Alpha: A New Role as a Transcription Factor. Sci Rep. 2, 980.

5. Vlahov, I. R., and Leamon, C. P. (2012) Engineering Folate-Drug Conjugates to Target Cancer: From Chemistry to Clinic. Bioconjug Chem. 23, 1357-1369.

6. Elwood, P. C. (1989) Molecular Cloning and Characterization of the Human Folate-Binding Protein cDNA from Placenta and Malignant Tissue Culture (KB) Cells. J Biol Chem. 264, 14893-14901.

7. Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., Puttmann, L., Vahid, L. N., Jensen, C., Moheb, L. A., Bienek, M., Larti, F., Mueller, I., Weissmann, R., Darvish, H., Wrogemann, K., Hadavi, V., Lipkowitz, B., Esmaeeli-Nieh, S., Wieczorek, D., Kariminejad, R., Firouzabadi, S. G., Cohen, M., Fattahi, Z., Rost, I., Mojahedi, F., Hertzberg, C., Dehghan, A., Rajab, A., Banavandi, M. J., Hoffer, J., Falah, M., Musante, L., Kalscheuer, V., Ullmann, R., Kuss, A. W., Tzschach, A., Kahrizi, K., and Ropers, H. H. (2011) Deep Sequencing Reveals 50 Novel Genes for Recessive Cognitive Disorders. Nature. 478, 57-63.

8. Ma, D. W., Finnell, R. H., Davidson, L. A., Callaway, E. S., Spiegelstein, O., Piedrahita, J. A., Salbaum, J. M., Kappen, C., Weeks, B. R., James, J., Bozinov, D., Lupton, J. R., and Chapkin, R. S. (2005) Folate Transport Gene Inactivation in Mice Increases Sensitivity to Colon Carcinogenesis. Cancer Res. 65, 887-897.

Posted On

2013-01-20

Science Writer

Anne Murray