Phenotypic Mutation 'potentes' (pdf version)
Allele | potentes |
Mutation Type |
missense
|
Chromosome | 8 |
Coordinate | 72,138,702 bp (GRCm39) |
Base Change | G ⇒ A (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 |
Alanine changed to Threonine
|
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 AA Change: A967T
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 damaging
PolyPhen 2
Score 0.985 (Sensitivity: 0.74; Specificity: 0.96)
(Using ENSMUST00000051995)
|
SMART Domains |
Protein: ENSMUSP00000105639 Gene: ENSMUSG00000031805 AA Change: A967T
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 damaging
PolyPhen 2
Score 0.985 (Sensitivity: 0.74; Specificity: 0.96)
(Using ENSMUST00000110012)
|
SMART Domains |
Protein: ENSMUSP00000105640 Gene: ENSMUSG00000031805 AA Change: A967T
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 damaging
PolyPhen 2
Score 0.985 (Sensitivity: 0.74; Specificity: 0.96)
(Using ENSMUST00000110013)
|
Meta Mutation Damage Score |
0.8205 |
Is this an essential gene? |
Possibly essential (E-score: 0.702) |
Phenotypic Category |
Unknown |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All Mutations and Alleles(30) : Chemically induced (ENU)(6) Chemically induced (other)(1) Gene trapped(14) Spontaneous(2) Targeted(5) Transgenic (2)
|
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 |
citron
|
UTSW |
8 |
72139620 |
splice site |
probably benign |
|
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 |
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 |
Unknown |
Local Stock | |
Repository | |
Last Updated |
2019-09-04 9:31 PM
by Anne Murray
|
Record Created |
2019-01-22 12:23 PM
by Bruce Beutler
|
Record Posted |
2019-02-01 |
Phenotypic Description |
The potentes phenotype was identified among G3 mice of the pedigree R5038, some of which showed increased CD4 to CD8 T cell ratios (Figure 1) due to increased frequencies of CD4+ T cells in CD3+ T cells (Figure 2) in the peripheral blood.
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 60 mutations. Both of the above anomalies were linked to a mutation in Jak3: a G to A transition at base pair 71,686,058 (v38) on chromosome 8, or base pair 9,676 in the GenBank genomic region NC_000074 encoding Jak3. The strongest association was found with a recessive model of inheritance to the CD4 to CD8 ratio phenotype (P = 0.000291), wherein three variant homozygotes departed phenotypically from 20 homozygous reference mice and 18 heterozygous mice (Figure 3). The mutation corresponds to residue 3,109 in the mRNA sequence NM_010589 within exon 21 of 25 total exons.
3094 GCGGACTTCGGCCTCGCTAAGCTGCTGCCCCTG
962 -A--D--F--G--L--A--K--L--L--P--L-
|
The mutated nucleotide is indicated in red. The mutation results in an alanine to threonine substitution at position 967 (A967T) in the JAK3 protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 0.985).
|
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 4; 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 potentes mutation results in an alanine to threonine substitution at position 967 (A967T) in the JAK3 protein; Ala967 is within the kinase domain. 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). The immune phenotype observed in the potentes mice indicates loss of JAK3-associated function.
|
Primers |
PCR Primer
potentes_pcr_F: CTGTTCGCTTGGCAGATCTG
potentes_pcr_R: ATCGTGGCTATAGGGCTGAC
Sequencing Primer
potentes_seq_F: GCAAGGTGCGAGCATCG
potentes_seq_R: CAAGGCCTTTGCGAGGG
|
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 424 nucleotides is amplified (chromosome 8, + strand):
1 ctgttcgctt ggcagatctg caaggtgcga gcatcgcgga gatcgggatg gggtctctgg 61 ggtccgggat cccgggccca cgtgctatca tggctctctg cagggcatgg agtacctggg 121 tgcgcgccgc tgcgtacacc gtgacctggc tgcgcgcaac atcttggtgg agagcgaggc 181 tcatgtgaag atcgcggact tcggcctcgc taagctgctg cccctgggaa aggactacta 241 cgtggtccgc gagcctggcc aaagccccat cttttggtac aagaccaaga ctccagacgt 301 cacgcccact gagccccaac tcccgcactc tacagcctta aaccggtcca gacccagctc 361 cacctcagta gctttgccct cgcaaaggcc ttgcccacag cagggtcagc cctatagcca 421 cgat
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References | 1. Wu, W., and Sun, X. H. (2012) Janus Kinase 3: The Controller and the Controlled. Acta Biochim Biophys Sin (Shanghai). 44, 187-196.
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 | Diantha La Vine |
Authors | Jin Huk Choi, Xue Zhong, and Bruce Beutler |