Phenotypic Mutation 'citron' (pdf version)
Allele | citron |
Mutation Type |
splice site
(4 bp from exon)
|
Chromosome | 8 |
Coordinate | 72,139,620 bp (GRCm39) |
Base Change | C ⇒ T (forward strand) |
Gene |
Jak3
|
Gene Name | Janus kinase 3 |
Chromosomal Location |
72,129,027-72,143,221 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 Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). [provided by RefSeq, Jul 2008] PHENOTYPE: Mice homozygous for a knock-out allele exhibit impaired B cell development, small thymi and T cell proliferate. Point mutation homozygotes develop autoimmune inflammatory bowel disease, decreased susceptibility to malaria infection and/or increased susceptibility to bacterial infection. [provided by MGI curators]
|
Accession Number | NCBI RefSeq: NM_010589; NM_001190830; MGI:99928
|
Mapped | Yes |
Amino Acid Change |
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000060073]
[ENSMUSP00000105639]
[ENSMUSP00000105640]
|
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000060073 Gene: ENSMUSG00000031805
Domain | Start | End | E-Value | Type |
B41
|
20 |
254 |
2.2e-42 |
SMART |
SH2
|
370 |
460 |
5.57e-8 |
SMART |
low complexity region
|
488 |
503 |
N/A |
INTRINSIC |
STYKc
|
517 |
773 |
3.58e-12 |
SMART |
TyrKc
|
818 |
1091 |
4.59e-105 |
SMART |
|
Predicted Effect |
probably benign
|
SMART Domains |
Protein: ENSMUSP00000105639 Gene: ENSMUSG00000031805
Domain | Start | End | E-Value | Type |
B41
|
20 |
254 |
2.2e-42 |
SMART |
SH2
|
370 |
460 |
5.57e-8 |
SMART |
low complexity region
|
488 |
503 |
N/A |
INTRINSIC |
STYKc
|
517 |
773 |
3.58e-12 |
SMART |
TyrKc
|
818 |
1091 |
4.59e-105 |
SMART |
|
Predicted Effect |
probably benign
|
SMART Domains |
Protein: ENSMUSP00000105640 Gene: ENSMUSG00000031805
Domain | Start | End | E-Value | Type |
B41
|
20 |
254 |
2.2e-42 |
SMART |
SH2
|
370 |
460 |
5.57e-8 |
SMART |
low complexity region
|
488 |
503 |
N/A |
INTRINSIC |
STYKc
|
517 |
773 |
3.58e-12 |
SMART |
TyrKc
|
818 |
1091 |
4.59e-105 |
SMART |
|
Predicted Effect |
probably benign
|
Meta Mutation Damage Score |
0.0898 |
Is this an essential gene? |
Possibly essential (E-score: 0.702) |
Phenotypic Category |
Autosomal Recessive |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All mutations/alleles(23) : Chemically induced (ENU)(3) Gene trapped(14) Spontaneous(1) Targeted(5)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00226:Jak3
|
APN |
8 |
72134341 |
splice site |
probably benign |
|
IGL00720:Jak3
|
APN |
8 |
72136681 |
missense |
probably damaging |
1.00 |
IGL00966:Jak3
|
APN |
8 |
72131656 |
missense |
probably benign |
0.24 |
IGL01147:Jak3
|
APN |
8 |
72136047 |
missense |
probably benign |
|
IGL01308:Jak3
|
APN |
8 |
72137810 |
missense |
probably damaging |
1.00 |
IGL01328:Jak3
|
APN |
8 |
72132264 |
missense |
probably damaging |
1.00 |
IGL01386:Jak3
|
APN |
8 |
72136933 |
missense |
probably damaging |
1.00 |
IGL01515:Jak3
|
APN |
8 |
72133206 |
splice site |
probably null |
|
IGL01870:Jak3
|
APN |
8 |
72133434 |
missense |
probably damaging |
1.00 |
IGL02132:Jak3
|
APN |
8 |
72131124 |
missense |
probably damaging |
0.99 |
IGL02413:Jak3
|
APN |
8 |
72138763 |
splice site |
probably null |
|
IGL02752:Jak3
|
APN |
8 |
72135595 |
missense |
possibly damaging |
0.50 |
IGL03089:Jak3
|
APN |
8 |
72138727 |
missense |
probably benign |
0.15 |
IGL03177:Jak3
|
APN |
8 |
72135014 |
missense |
probably damaging |
1.00 |
barbed
|
UTSW |
8 |
72131425 |
missense |
possibly damaging |
0.88 |
beanstalk
|
UTSW |
8 |
72139932 |
missense |
probably benign |
0.01 |
Bonis
|
UTSW |
8 |
72131898 |
missense |
probably benign |
0.05 |
corrupt
|
UTSW |
8 |
72136696 |
missense |
probably damaging |
1.00 |
daniels
|
UTSW |
8 |
72134299 |
missense |
possibly damaging |
0.48 |
Deposuit
|
UTSW |
8 |
72138048 |
missense |
probably damaging |
1.00 |
distortion
|
UTSW |
8 |
72136622 |
missense |
probably damaging |
1.00 |
Downcast
|
UTSW |
8 |
72138155 |
missense |
probably benign |
0.07 |
fake_news
|
UTSW |
8 |
72138601 |
missense |
probably damaging |
1.00 |
Implevit
|
UTSW |
8 |
72131417 |
missense |
probably benign |
|
mount_tai
|
UTSW |
8 |
72136021 |
missense |
probably damaging |
1.00 |
potentes
|
UTSW |
8 |
72138702 |
missense |
probably damaging |
0.99 |
Riot
|
UTSW |
8 |
72134960 |
missense |
probably damaging |
1.00 |
thistle
|
UTSW |
8 |
72138027 |
critical splice acceptor site |
probably null |
|
thistle2
|
UTSW |
8 |
72138189 |
missense |
probably damaging |
1.00 |
PIT4403001:Jak3
|
UTSW |
8 |
72136993 |
missense |
probably benign |
0.00 |
PIT4515001:Jak3
|
UTSW |
8 |
72132286 |
missense |
probably benign |
0.21 |
R0013:Jak3
|
UTSW |
8 |
72136971 |
missense |
probably damaging |
0.98 |
R0496:Jak3
|
UTSW |
8 |
72135041 |
missense |
probably damaging |
1.00 |
R0522:Jak3
|
UTSW |
8 |
72134918 |
splice site |
probably benign |
|
R0531:Jak3
|
UTSW |
8 |
72139620 |
splice site |
probably benign |
|
R0538:Jak3
|
UTSW |
8 |
72138126 |
missense |
probably benign |
|
R0612:Jak3
|
UTSW |
8 |
72136021 |
missense |
probably damaging |
1.00 |
R0744:Jak3
|
UTSW |
8 |
72136622 |
missense |
probably damaging |
1.00 |
R0833:Jak3
|
UTSW |
8 |
72136622 |
missense |
probably damaging |
1.00 |
R0836:Jak3
|
UTSW |
8 |
72136622 |
missense |
probably damaging |
1.00 |
R1183:Jak3
|
UTSW |
8 |
72137194 |
missense |
probably damaging |
1.00 |
R1420:Jak3
|
UTSW |
8 |
72134182 |
missense |
possibly damaging |
0.75 |
R1793:Jak3
|
UTSW |
8 |
72138590 |
splice site |
probably benign |
|
R1967:Jak3
|
UTSW |
8 |
72134179 |
missense |
probably damaging |
1.00 |
R1983:Jak3
|
UTSW |
8 |
72140780 |
missense |
probably benign |
|
R1983:Jak3
|
UTSW |
8 |
72131019 |
missense |
possibly damaging |
0.95 |
R2058:Jak3
|
UTSW |
8 |
72138027 |
critical splice acceptor site |
probably null |
|
R2060:Jak3
|
UTSW |
8 |
72136059 |
nonsense |
probably null |
|
R2060:Jak3
|
UTSW |
8 |
72133358 |
nonsense |
probably null |
|
R3705:Jak3
|
UTSW |
8 |
72134166 |
missense |
probably damaging |
1.00 |
R3734:Jak3
|
UTSW |
8 |
72129225 |
unclassified |
probably benign |
|
R4231:Jak3
|
UTSW |
8 |
72138189 |
missense |
probably damaging |
1.00 |
R4596:Jak3
|
UTSW |
8 |
72137275 |
missense |
probably damaging |
0.99 |
R4844:Jak3
|
UTSW |
8 |
72134299 |
missense |
possibly damaging |
0.48 |
R4897:Jak3
|
UTSW |
8 |
72138048 |
missense |
probably damaging |
1.00 |
R5038:Jak3
|
UTSW |
8 |
72138702 |
missense |
probably damaging |
0.99 |
R5469:Jak3
|
UTSW |
8 |
72131417 |
missense |
probably benign |
|
R5538:Jak3
|
UTSW |
8 |
72131417 |
missense |
probably benign |
|
R5718:Jak3
|
UTSW |
8 |
72136998 |
missense |
probably damaging |
1.00 |
R5799:Jak3
|
UTSW |
8 |
72131344 |
missense |
probably damaging |
1.00 |
R5909:Jak3
|
UTSW |
8 |
72136875 |
missense |
possibly damaging |
0.68 |
R5959:Jak3
|
UTSW |
8 |
72134715 |
missense |
probably damaging |
1.00 |
R6260:Jak3
|
UTSW |
8 |
72131954 |
missense |
probably benign |
0.00 |
R6798:Jak3
|
UTSW |
8 |
72133615 |
missense |
probably damaging |
0.99 |
R7013:Jak3
|
UTSW |
8 |
72131425 |
missense |
possibly damaging |
0.88 |
R7070:Jak3
|
UTSW |
8 |
72137255 |
missense |
probably damaging |
1.00 |
R7122:Jak3
|
UTSW |
8 |
72138601 |
missense |
probably damaging |
1.00 |
R7166:Jak3
|
UTSW |
8 |
72134960 |
missense |
probably damaging |
1.00 |
R7225:Jak3
|
UTSW |
8 |
72138155 |
missense |
probably benign |
0.07 |
R7440:Jak3
|
UTSW |
8 |
72133362 |
missense |
probably benign |
0.02 |
R7489:Jak3
|
UTSW |
8 |
72136936 |
missense |
probably damaging |
1.00 |
R7773:Jak3
|
UTSW |
8 |
72131686 |
missense |
probably benign |
|
R7779:Jak3
|
UTSW |
8 |
72139932 |
missense |
probably benign |
0.01 |
R8511:Jak3
|
UTSW |
8 |
72138194 |
missense |
probably damaging |
1.00 |
R8808:Jak3
|
UTSW |
8 |
72138164 |
missense |
possibly damaging |
0.71 |
R8859:Jak3
|
UTSW |
8 |
72131160 |
missense |
probably benign |
0.37 |
R9079:Jak3
|
UTSW |
8 |
72131898 |
missense |
probably benign |
0.05 |
R9320:Jak3
|
UTSW |
8 |
72134265 |
missense |
probably benign |
0.03 |
R9389:Jak3
|
UTSW |
8 |
72136696 |
missense |
probably damaging |
1.00 |
R9664:Jak3
|
UTSW |
8 |
72131366 |
missense |
probably damaging |
1.00 |
Z1176:Jak3
|
UTSW |
8 |
72133327 |
missense |
possibly damaging |
0.93 |
|
Mode of Inheritance |
Autosomal Recessive |
Local Stock | gDNA |
MMRRC Submission |
038161-MU
|
Last Updated |
2019-09-04 9:48 PM
by Diantha La Vine
|
Record Created |
2014-06-14 10:20 PM
by Ming Zeng
|
Record Posted |
2015-02-11 |
Phenotypic Description |
The citron phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R0531, some of which showed an increase in the B:T cell ratio (Figure 1) due to an increased frequency of B cells (Figure 2) as well as an increased frequency of IgM+ B cells (Figure 3) and a higher percentage of IgD+ B cells (Figure 4), all in the peripheral blood.
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 74 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Jak3: a C to T transition at base pair 71,686,976 (v38) on chromosome 8, or base pair 10,594 in the GenBank genomic region NC_000074 encoding Jak3. The strongest association was found with a recessive model of linkage to the normalized B cell frequency, wherein three variant homozygotes departed phenotypically from six homozygous reference mice and 11 heterozygous mice with a P value of 2.244 x 10-7 (Figure 5). The mutation is located within the donor splice site of intron 22, four nucleotides from the previous exon. Two Jak3 protein-coding transcripts are displayed on Ensembl; both transcripts encode the same protein. The effect of the mutation at the cDNA and protein level is unknown. One possibility, shown below, is that aberrant splicing would cause skipping of the 118 base pair exon 22 (out of 25 total exons; exon 22 encodes amino acids 990-1028) and a frame-shift that results in coding of two aberrant amino acids followed by a premature stop codon in exon 23.
<--exon 21 <--exon 22 intron 22--> exon 23-->
9733 ……CCCATCTTTTG ………AGCCCATCCGCT gtgcgtcgcctgc……… GAGTTCCTGA 10866
986 ……-P--I--F--W ………-S--P--S--A- --S--S--* 991
correct deleted aberrant
|
Genomic numbering corresponds to NC_000074. The donor splice site of intron 22, which is destroyed by the mutation, is indicated in blue; the mutated nucleotide is indicated in red.
|
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
Jak3 encodes Janus kinase 3 (JAK3). JAK3 has seven different highly conserved JAK homology (JH) regions (JH1-JH7) [Figure 6; reviewed in (1)]. The JH1 region is the kinase domain (amino acids 818-1091), the JH2 domain corresponds to the pseudokinase domain (amino acids 517-773), the JH3 and JH4 regions comprise an Src Homology 2 (SH2)-like domain (amino acids 370-460), and the JH6 and JH7 regions consist of a 4.1, ezrin, radixin, moesin (FERM) homology domain (alternatively, B41 domain; amino acids 20-254). The citron mutation is predicted to result in deletion of exon 22 which encodes amino acids 990-1023 within the JAK3 kinase domain, a frame-shift, and coding of a premature stop codon within the JAK3 kinase domain. Expression and localization of JAK3citron have not been examined. Please see the record mount_tai for more information about Jak3.
|
Putative Mechanism | JAK3 binding is restricted to hematopoietic-specific cytokine receptors that have a γc receptor subunit (i.e., the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors) [reviewed in (1)]. The γc receptor-associated cytokines have known functions. For example, IL-7 is necessary for T and B cell development, IL-2 functions in peripheral T cell homeostasis and antigen-driven T-cell expansion, IL-15 functions in natural killer (NK) cell differentiation, IL-4 functions in B-cell maturation and isotype switching (2). JAK3 mutations result in defective γc receptor-associated signaling and subsequent defects in lymphocyte development (2;3). Mutations in JAK3 are linked to autosomal recessive T- and NK-cell negative/B-cell positive type of severe combined immunodeficiency [T−B+NK- SCID; OMIM: #600802; (4-6); reviewed in (2)]. Patients with T−B+NK- SCID do not have T or NK cells, but have normal to elevated numbers of immature nonfunctional B lymphocytes (5;6). Patients with SCID have persistent, recurring infections due to loss of T cell-associated immunity. Jak3 knockout (Jak3-/-) mice have reduced numbers of T, B, γδ T, and NK cells (7-11). B cell maturation in the Jak3-/- mice is blocked at the pre-B stage, leading to a reduced frequency of IgM+ B cells (10). In contrast to Jak3-/- mice, citron mice exhibit increased frequencies of IgM+ B cells. Similar to patients with T−B+NK- SCID, the citron mice have increased frequencies of peripheral B cells, including the IgM+ and IgD+ B cells; however the frequency of peripheral T and NK cells were comparable between the citron and wild-type mice, indicating that JAK3citron may retain some function.
|
Primers |
PCR Primer
citron_pcr_F: GCCATACTTCACATTGACGACTCCC
citron_pcr_R: AAAGTATTCCCAGTCAGGCACCGC
Sequencing Primer
citron_seq_F: AGGCCACTGTTTCACACC
citron_seq_R: ATCATGCTCAGGAACTCCTGTG
|
Genotyping | 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 665 nucleotides is amplified (chromosome 8, + strand):
1 gccatacttc acattgacga ctccctcccc aggccactgt ttcacaccct gcccactctc 61 ctcactggcc acaccacacc tctgtccggc tctcaggtat gccccggagt ccctatctga 121 caacatcttc tcccgccaat ctgacgtgtg gagcttcgga gtggtgttgt acgagctctt 181 cacctactgc gacaagagct gcagcccatc cgctgtgcgt cgcctgcccc atccctcggt 241 cctccctctt gatctccaaa tcccctcctg acctctagcc cctatcctga ccccagccct 301 tcctcctgac ctccagatca tctcctgacc tcagtcctcc ctccggaatc ccagcccttc 361 ctcctcatct ccagatccct tcttgacccc agcccttccc ctgaccccca gcccttcctc 421 atgacgtcag cccccttcct gaccctaaca gtcctgccct aacttgctcc tctcccacag 481 gagttcctga gcatgatggg gcctgagcgt gaaggacccc cgctctgccg cctcctggag 541 ctgctggcag agggccgacg cctcccacca cctcccacct gccccaccga ggtgaggaag 601 gaggactcaa gtttctcagt ttcaattctt gattgacagc agcggtgcct gactgggaat 661 acttt
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References |
2. Notarangelo, L. D., Mella, P., Jones, A., de Saint Basile, G., Savoldi, G., Cranston, T., Vihinen, M., and Schumacher, R. F. (2001) Mutations in Severe Combined Immune Deficiency (SCID) due to JAK3 Deficiency. Hum Mutat. 18, 255-263.
4. Candotti, F., Oakes, S. A., Johnston, J. A., Giliani, S., Schumacher, R. F., Mella, P., Fiorini, M., Ugazio, A. G., Badolato, R., Notarangelo, L. D., Bozzi, F., Macchi, P., Strina, D., Vezzoni, P., Blaese, R. M., O'Shea, J. J., and Villa, A. (1997) Structural and Functional Basis for JAK3-Deficient Severe Combined Immunodeficiency. Blood. 90, 3996-4003.
5. Macchi, P., Villa, A., Giliani, S., Sacco, M. G., Frattini, A., Porta, F., Ugazio, A. G., Johnston, J. A., Candotti, F., and O'Shea, J. J. (1995) Mutations of Jak-3 Gene in Patients with Autosomal Severe Combined Immune Deficiency (SCID). Nature. 377, 65-68.
6. Russell, S. M., Tayebi, N., Nakajima, H., Riedy, M. C., Roberts, J. L., Aman, M. J., Migone, T. S., Noguchi, M., Markert, M. L., Buckley, R. H., O'Shea, J. J., and Leonard, W. J. (1995) Mutation of Jak3 in a Patient with SCID: Essential Role of Jak3 in Lymphoid Development. Science. 270, 797-800.
7. Nosaka, T., van Deursen, J. M., Tripp, R. A., Thierfelder, W. E., Witthuhn, B. A., McMickle, A. P., Doherty, P. C., Grosveld, G. C., and Ihle, J. N. (1995) Defective Lymphoid Development in Mice Lacking Jak3. Science. 270, 800-802.
8. Park, S. Y., Saijo, K., Takahashi, T., Osawa, M., Arase, H., Hirayama, N., Miyake, K., Nakauchi, H., Shirasawa, T., and Saito, T. (1995) Developmental Defects of Lymphoid Cells in Jak3 Kinase-Deficient Mice. Immunity. 3, 771-782.
10. Thomis, D. C., Gurniak, C. B., Tivol, E., Sharpe, A. H., and Berg, L. J. (1995) Defects in B Lymphocyte Maturation and T Lymphocyte Activation in Mice Lacking Jak3. Science. 270, 794-797.
11. Eynon, E. E., Livak, F., Kuida, K., Schatz, D. G., and Flavell, R. A. (1999) Distinct Effects of Jak3 Signaling on Alphabeta and Gammadelta Thymocyte Development. J Immunol. 162, 1448-1459.
|
Science Writers | Anne Murray |
Illustrators | Peter Jurek |
Authors | Ming Zeng, Kuan-Wen Wang, Jin Huk Choi, Bruce Beutler |