Phenotypic Mutation 'samarai' (pdf version)
Allele | samarai |
Mutation Type |
critical splice donor site
(1 bp from exon)
|
Chromosome | 15 |
Coordinate | 66,629,855 bp (GRCm39) |
Base Change | G ⇒ A (forward strand) |
Gene |
Tg
|
Gene Name | thyroglobulin |
Synonym(s) | Tgn |
Chromosomal Location |
66,542,606-66,722,570 bp (+) (GRCm39)
|
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] Thyroglobulin (Tg) is a glycoprotein homodimer produced predominantly by the thryroid gland. It acts as a substrate for the synthesis of thyroxine and triiodothyronine as well as the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to its site of iodination, and subsequent thyroxine biosynthesis, in the follicular lumen. Mutations in this gene cause thyroid dyshormonogenesis, manifested as goiter, and are associated with moderate to severe congenital hypothyroidism. Polymorphisms in this gene are associated with susceptibility to autoimmune thyroid diseases (AITD) such as Graves disease and Hashimoto thryoiditis. [provided by RefSeq, Nov 2009] PHENOTYPE: Mice homozygous for a spontaneous mutation exhibit enlarged thyroid gland, hypothyroidism, abnormal thyroid gland morphology, and decreased body weight. [provided by MGI curators]
|
Accession Number | NCBI RefSeq: NM_027902; MGI:1919003
|
Mapped | Yes |
Amino Acid Change |
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000070239 †]
[ENSMUSP00000129868 †]
[ENSMUSP00000126454 †]
† probably from a misspliced transcript
|
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000070239 Gene: ENSMUSG00000053469
Domain | Start | End | E-Value | Type |
signal peptide
|
1 |
20 |
N/A |
INTRINSIC |
TY
|
50 |
97 |
5.9e-16 |
SMART |
TY
|
118 |
165 |
5.59e-17 |
SMART |
Pfam:Thyroglobulin_1
|
174 |
252 |
4e-9 |
PFAM |
TY
|
317 |
363 |
4.36e-19 |
SMART |
low complexity region
|
495 |
504 |
N/A |
INTRINSIC |
TY
|
617 |
662 |
3.58e-15 |
SMART |
TY
|
684 |
730 |
1.47e-16 |
SMART |
TY
|
880 |
926 |
1.51e-4 |
SMART |
TY
|
1029 |
1078 |
1.21e-12 |
SMART |
TY
|
1106 |
1150 |
7.56e-5 |
SMART |
TY
|
1167 |
1215 |
7.26e-16 |
SMART |
low complexity region
|
1244 |
1255 |
N/A |
INTRINSIC |
Pfam:GCC2_GCC3
|
1464 |
1509 |
2.7e-16 |
PFAM |
TY
|
1519 |
1568 |
9.81e-13 |
SMART |
Pfam:COesterase
|
2181 |
2717 |
8.4e-140 |
PFAM |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000129868 Gene: ENSMUSG00000053469
Domain | Start | End | E-Value | Type |
TY
|
14 |
63 |
1.21e-12 |
SMART |
|
Predicted Effect |
noncoding transcript
|
SMART Domains |
Protein: ENSMUSP00000126454 Gene: ENSMUSG00000053469
Domain | Start | End | E-Value | Type |
internal_repeat_1
|
93 |
331 |
1.53e-6 |
PROSPERO |
Pfam:COesterase
|
562 |
1098 |
2.1e-137 |
PFAM |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000126454 Gene: ENSMUSG00000053469
Domain | Start | End | E-Value | Type |
internal_repeat_1
|
93 |
331 |
1.53e-6 |
PROSPERO |
Pfam:COesterase
|
562 |
1098 |
2.1e-137 |
PFAM |
|
Predicted Effect |
probably null
|
SMART Domains |
Protein: ENSMUSP00000128410 Gene: ENSMUSG00000053469
Domain | Start | End | E-Value | Type |
Pfam:COesterase
|
313 |
849 |
6e-140 |
PFAM |
|
Predicted Effect |
noncoding transcript
|
SMART Domains |
Protein: ENSMUSP00000128410 Gene: ENSMUSG00000053469
Domain | Start | End | E-Value | Type |
Pfam:COesterase
|
313 |
849 |
6e-140 |
PFAM |
|
Predicted Effect |
noncoding transcript
|
Meta Mutation Damage Score |
0.9469 |
Is this an essential gene? |
Probably nonessential (E-score: 0.096) |
Phenotypic Category |
Unknown |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All Mutations and Alleles(14) : Chemically induced (ENU)(4) Chemically induced (other)(3) Endonuclease-mediated(1) Gene trapped(1) Radiation induced(2) Spontaneous(1) Targeted(1) Transgenic(1)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00157:Tg
|
APN |
15 |
66719015 |
missense |
probably damaging |
1.00 |
IGL00230:Tg
|
APN |
15 |
66699139 |
missense |
probably benign |
0.00 |
IGL00324:Tg
|
APN |
15 |
66565273 |
missense |
probably benign |
|
IGL00428:Tg
|
APN |
15 |
66645273 |
missense |
probably benign |
0.33 |
IGL00703:Tg
|
APN |
15 |
66568338 |
missense |
probably benign |
0.34 |
IGL00808:Tg
|
APN |
15 |
66555662 |
missense |
probably damaging |
1.00 |
IGL00833:Tg
|
APN |
15 |
66560650 |
missense |
probably benign |
0.34 |
IGL00899:Tg
|
APN |
15 |
66545922 |
critical splice donor site |
probably null |
|
IGL00921:Tg
|
APN |
15 |
66636302 |
missense |
probably benign |
0.28 |
IGL00975:Tg
|
APN |
15 |
66553731 |
missense |
probably benign |
|
IGL01288:Tg
|
APN |
15 |
66608125 |
missense |
possibly damaging |
0.81 |
IGL01397:Tg
|
APN |
15 |
66567941 |
splice site |
probably benign |
|
IGL01634:Tg
|
APN |
15 |
66601415 |
missense |
probably benign |
0.34 |
IGL01646:Tg
|
APN |
15 |
66549936 |
missense |
probably damaging |
1.00 |
IGL01704:Tg
|
APN |
15 |
66543200 |
missense |
probably damaging |
0.98 |
IGL01958:Tg
|
APN |
15 |
66631335 |
missense |
probably benign |
0.06 |
IGL02093:Tg
|
APN |
15 |
66564223 |
missense |
possibly damaging |
0.83 |
IGL02113:Tg
|
APN |
15 |
66577179 |
missense |
probably benign |
0.08 |
IGL02138:Tg
|
APN |
15 |
66589082 |
missense |
probably benign |
0.01 |
IGL02156:Tg
|
APN |
15 |
66577197 |
missense |
probably benign |
0.19 |
IGL02169:Tg
|
APN |
15 |
66629792 |
missense |
probably benign |
0.04 |
IGL02342:Tg
|
APN |
15 |
66636140 |
missense |
probably benign |
|
IGL02434:Tg
|
APN |
15 |
66636191 |
missense |
probably damaging |
0.97 |
IGL02506:Tg
|
APN |
15 |
66613443 |
missense |
possibly damaging |
0.71 |
IGL02513:Tg
|
APN |
15 |
66577123 |
missense |
probably benign |
|
IGL02549:Tg
|
APN |
15 |
66711210 |
missense |
probably damaging |
1.00 |
IGL02669:Tg
|
APN |
15 |
66620575 |
splice site |
probably benign |
|
IGL02756:Tg
|
APN |
15 |
66606435 |
missense |
probably benign |
|
IGL02800:Tg
|
APN |
15 |
66629735 |
missense |
probably damaging |
1.00 |
IGL02828:Tg
|
APN |
15 |
66554243 |
missense |
probably damaging |
1.00 |
IGL02927:Tg
|
APN |
15 |
66549942 |
missense |
probably damaging |
1.00 |
IGL03061:Tg
|
APN |
15 |
66543254 |
missense |
probably damaging |
1.00 |
IGL03105:Tg
|
APN |
15 |
66586955 |
missense |
probably benign |
0.01 |
IGL03160:Tg
|
APN |
15 |
66711152 |
nonsense |
probably null |
|
IGL03242:Tg
|
APN |
15 |
66555647 |
missense |
probably damaging |
0.99 |
Also_ran
|
UTSW |
15 |
66550688 |
missense |
probably damaging |
1.00 |
bedraggled
|
UTSW |
15 |
66612563 |
missense |
probably damaging |
1.00 |
foster
|
UTSW |
15 |
66565109 |
nonsense |
probably null |
|
hognose
|
UTSW |
15 |
66589057 |
missense |
probably damaging |
0.99 |
ito
|
UTSW |
15 |
66638011 |
nonsense |
probably null |
|
ito2
|
UTSW |
15 |
66543245 |
missense |
probably damaging |
1.00 |
ito3
|
UTSW |
15 |
66645323 |
missense |
probably damaging |
1.00 |
ito4
|
UTSW |
15 |
66568369 |
missense |
possibly damaging |
0.47 |
Papua
|
UTSW |
15 |
66545899 |
missense |
probably damaging |
1.00 |
Pipistrella
|
UTSW |
15 |
66567984 |
missense |
probably damaging |
1.00 |
pluribus
|
UTSW |
15 |
66587012 |
missense |
probably damaging |
0.98 |
sariba
|
UTSW |
15 |
66566719 |
missense |
probably benign |
0.01 |
ticker
|
UTSW |
15 |
66699231 |
nonsense |
probably null |
|
Vampire
|
UTSW |
15 |
66554676 |
missense |
probably damaging |
1.00 |
IGL03134:Tg
|
UTSW |
15 |
66612567 |
missense |
probably damaging |
1.00 |
P0019:Tg
|
UTSW |
15 |
66560712 |
missense |
probably benign |
0.01 |
R0121:Tg
|
UTSW |
15 |
66612630 |
missense |
probably benign |
0.04 |
R0135:Tg
|
UTSW |
15 |
66566719 |
missense |
probably benign |
0.01 |
R0227:Tg
|
UTSW |
15 |
66570295 |
missense |
possibly damaging |
0.84 |
R0448:Tg
|
UTSW |
15 |
66636291 |
missense |
probably damaging |
1.00 |
R0453:Tg
|
UTSW |
15 |
66700382 |
missense |
probably benign |
0.09 |
R0504:Tg
|
UTSW |
15 |
66554253 |
missense |
probably damaging |
0.97 |
R0543:Tg
|
UTSW |
15 |
66601446 |
missense |
probably benign |
0.13 |
R0638:Tg
|
UTSW |
15 |
66589057 |
missense |
probably damaging |
0.99 |
R0639:Tg
|
UTSW |
15 |
66613333 |
critical splice acceptor site |
probably null |
|
R0646:Tg
|
UTSW |
15 |
66601475 |
missense |
probably damaging |
0.99 |
R0666:Tg
|
UTSW |
15 |
66609370 |
missense |
probably benign |
|
R0673:Tg
|
UTSW |
15 |
66613333 |
critical splice acceptor site |
probably null |
|
R0689:Tg
|
UTSW |
15 |
66711253 |
splice site |
probably benign |
|
R0704:Tg
|
UTSW |
15 |
66629729 |
missense |
probably benign |
0.02 |
R0730:Tg
|
UTSW |
15 |
66550638 |
missense |
probably damaging |
1.00 |
R0830:Tg
|
UTSW |
15 |
66596993 |
missense |
probably damaging |
1.00 |
R0959:Tg
|
UTSW |
15 |
66579859 |
missense |
probably damaging |
0.98 |
R1027:Tg
|
UTSW |
15 |
66544258 |
missense |
possibly damaging |
0.65 |
R1061:Tg
|
UTSW |
15 |
66570408 |
missense |
probably benign |
0.09 |
R1086:Tg
|
UTSW |
15 |
66555911 |
missense |
probably benign |
|
R1103:Tg
|
UTSW |
15 |
66591504 |
missense |
probably benign |
0.45 |
R1240:Tg
|
UTSW |
15 |
66700397 |
missense |
probably benign |
0.16 |
R1281:Tg
|
UTSW |
15 |
66568338 |
missense |
probably benign |
0.34 |
R1470:Tg
|
UTSW |
15 |
66721312 |
missense |
possibly damaging |
0.95 |
R1470:Tg
|
UTSW |
15 |
66721312 |
missense |
possibly damaging |
0.95 |
R1531:Tg
|
UTSW |
15 |
66722351 |
missense |
probably benign |
0.02 |
R1544:Tg
|
UTSW |
15 |
66577081 |
missense |
probably benign |
0.04 |
R1550:Tg
|
UTSW |
15 |
66565279 |
missense |
possibly damaging |
0.52 |
R1575:Tg
|
UTSW |
15 |
66601534 |
critical splice donor site |
probably null |
|
R1638:Tg
|
UTSW |
15 |
66568015 |
nonsense |
probably null |
|
R1655:Tg
|
UTSW |
15 |
66700417 |
critical splice donor site |
probably null |
|
R1671:Tg
|
UTSW |
15 |
66564236 |
missense |
possibly damaging |
0.89 |
R1789:Tg
|
UTSW |
15 |
66609397 |
missense |
probably benign |
0.00 |
R1883:Tg
|
UTSW |
15 |
66543158 |
missense |
probably damaging |
1.00 |
R1984:Tg
|
UTSW |
15 |
66554691 |
missense |
probably benign |
|
R2063:Tg
|
UTSW |
15 |
66700402 |
missense |
probably damaging |
1.00 |
R2092:Tg
|
UTSW |
15 |
66721456 |
missense |
probably null |
0.26 |
R2109:Tg
|
UTSW |
15 |
66601443 |
missense |
probably benign |
0.02 |
R2128:Tg
|
UTSW |
15 |
66566743 |
missense |
probably benign |
0.10 |
R2129:Tg
|
UTSW |
15 |
66566743 |
missense |
probably benign |
0.10 |
R2207:Tg
|
UTSW |
15 |
66553788 |
missense |
probably benign |
0.15 |
R2219:Tg
|
UTSW |
15 |
66553782 |
missense |
probably benign |
0.03 |
R2228:Tg
|
UTSW |
15 |
66545860 |
missense |
probably damaging |
0.99 |
R2229:Tg
|
UTSW |
15 |
66545860 |
missense |
probably damaging |
0.99 |
R2259:Tg
|
UTSW |
15 |
66555747 |
missense |
probably benign |
|
R2994:Tg
|
UTSW |
15 |
66553802 |
missense |
probably benign |
|
R3904:Tg
|
UTSW |
15 |
66638011 |
nonsense |
probably null |
|
R3946:Tg
|
UTSW |
15 |
66545872 |
missense |
probably damaging |
1.00 |
R3965:Tg
|
UTSW |
15 |
66556039 |
missense |
probably benign |
|
R4245:Tg
|
UTSW |
15 |
66568318 |
missense |
possibly damaging |
0.68 |
R4451:Tg
|
UTSW |
15 |
66637996 |
missense |
probably benign |
0.01 |
R4487:Tg
|
UTSW |
15 |
66543245 |
missense |
probably damaging |
1.00 |
R4489:Tg
|
UTSW |
15 |
66579791 |
missense |
probably damaging |
1.00 |
R4623:Tg
|
UTSW |
15 |
66607120 |
missense |
probably benign |
0.23 |
R4659:Tg
|
UTSW |
15 |
66545769 |
missense |
possibly damaging |
0.67 |
R4728:Tg
|
UTSW |
15 |
66554676 |
missense |
probably damaging |
1.00 |
R4760:Tg
|
UTSW |
15 |
66565168 |
missense |
probably damaging |
1.00 |
R4797:Tg
|
UTSW |
15 |
66629855 |
critical splice donor site |
probably null |
|
R4944:Tg
|
UTSW |
15 |
66636186 |
missense |
probably damaging |
1.00 |
R4998:Tg
|
UTSW |
15 |
66545899 |
missense |
probably damaging |
1.00 |
R5009:Tg
|
UTSW |
15 |
66568435 |
missense |
probably benign |
0.01 |
R5025:Tg
|
UTSW |
15 |
66579779 |
missense |
probably damaging |
1.00 |
R5035:Tg
|
UTSW |
15 |
66553662 |
splice site |
probably null |
|
R5049:Tg
|
UTSW |
15 |
66699231 |
nonsense |
probably null |
|
R5073:Tg
|
UTSW |
15 |
66607101 |
missense |
probably benign |
0.05 |
R5169:Tg
|
UTSW |
15 |
66550629 |
nonsense |
probably null |
|
R5185:Tg
|
UTSW |
15 |
66645323 |
missense |
probably damaging |
1.00 |
R5227:Tg
|
UTSW |
15 |
66631416 |
missense |
possibly damaging |
0.87 |
R5300:Tg
|
UTSW |
15 |
66550704 |
missense |
probably damaging |
1.00 |
R5334:Tg
|
UTSW |
15 |
66549904 |
missense |
probably damaging |
1.00 |
R5339:Tg
|
UTSW |
15 |
66549942 |
missense |
probably damaging |
1.00 |
R5402:Tg
|
UTSW |
15 |
66611017 |
missense |
probably damaging |
0.98 |
R5441:Tg
|
UTSW |
15 |
66568369 |
missense |
possibly damaging |
0.47 |
R5509:Tg
|
UTSW |
15 |
66699142 |
missense |
probably benign |
0.45 |
R5580:Tg
|
UTSW |
15 |
66557149 |
missense |
possibly damaging |
0.66 |
R5582:Tg
|
UTSW |
15 |
66565284 |
missense |
probably damaging |
1.00 |
R5624:Tg
|
UTSW |
15 |
66709906 |
missense |
probably benign |
0.11 |
R5686:Tg
|
UTSW |
15 |
66560738 |
missense |
probably benign |
0.28 |
R6042:Tg
|
UTSW |
15 |
66555842 |
missense |
probably benign |
0.01 |
R6122:Tg
|
UTSW |
15 |
66700306 |
missense |
probably damaging |
1.00 |
R6146:Tg
|
UTSW |
15 |
66545216 |
splice site |
probably null |
|
R6159:Tg
|
UTSW |
15 |
66607096 |
missense |
possibly damaging |
0.71 |
R6223:Tg
|
UTSW |
15 |
66579771 |
missense |
probably benign |
0.15 |
R6480:Tg
|
UTSW |
15 |
66543160 |
missense |
probably damaging |
1.00 |
R6505:Tg
|
UTSW |
15 |
66631407 |
missense |
probably damaging |
0.99 |
R6531:Tg
|
UTSW |
15 |
66711211 |
missense |
probably damaging |
0.99 |
R6614:Tg
|
UTSW |
15 |
66607108 |
missense |
probably damaging |
0.99 |
R6698:Tg
|
UTSW |
15 |
66711211 |
missense |
probably damaging |
1.00 |
R6798:Tg
|
UTSW |
15 |
66550688 |
missense |
probably damaging |
1.00 |
R6837:Tg
|
UTSW |
15 |
66567984 |
missense |
probably damaging |
1.00 |
R6861:Tg
|
UTSW |
15 |
66560740 |
missense |
probably benign |
0.00 |
R6888:Tg
|
UTSW |
15 |
66568095 |
missense |
probably damaging |
0.99 |
R6933:Tg
|
UTSW |
15 |
66636158 |
missense |
possibly damaging |
0.73 |
R6983:Tg
|
UTSW |
15 |
66565207 |
missense |
probably benign |
0.01 |
R7078:Tg
|
UTSW |
15 |
66545392 |
missense |
probably damaging |
1.00 |
R7244:Tg
|
UTSW |
15 |
66612563 |
missense |
probably damaging |
1.00 |
R7320:Tg
|
UTSW |
15 |
66566633 |
missense |
possibly damaging |
0.71 |
R7334:Tg
|
UTSW |
15 |
66597121 |
missense |
probably benign |
0.01 |
R7418:Tg
|
UTSW |
15 |
66568432 |
missense |
probably damaging |
0.99 |
R7485:Tg
|
UTSW |
15 |
66568437 |
missense |
probably benign |
0.04 |
R7524:Tg
|
UTSW |
15 |
66568010 |
missense |
probably benign |
0.01 |
R7529:Tg
|
UTSW |
15 |
66566617 |
missense |
probably damaging |
0.99 |
R7540:Tg
|
UTSW |
15 |
66561776 |
missense |
probably benign |
0.16 |
R7583:Tg
|
UTSW |
15 |
66636267 |
missense |
probably damaging |
1.00 |
R7594:Tg
|
UTSW |
15 |
66601432 |
missense |
probably benign |
0.20 |
R7667:Tg
|
UTSW |
15 |
66587012 |
missense |
probably damaging |
0.98 |
R7722:Tg
|
UTSW |
15 |
66636158 |
missense |
possibly damaging |
0.73 |
R7790:Tg
|
UTSW |
15 |
66721453 |
missense |
probably damaging |
0.99 |
R7838:Tg
|
UTSW |
15 |
66565112 |
missense |
probably benign |
0.00 |
R7890:Tg
|
UTSW |
15 |
66555663 |
missense |
probably damaging |
1.00 |
R7904:Tg
|
UTSW |
15 |
66577128 |
missense |
probably benign |
0.08 |
R7919:Tg
|
UTSW |
15 |
66555923 |
missense |
possibly damaging |
0.73 |
R7921:Tg
|
UTSW |
15 |
66555642 |
missense |
probably benign |
0.08 |
R8037:Tg
|
UTSW |
15 |
66560724 |
missense |
probably benign |
0.00 |
R8038:Tg
|
UTSW |
15 |
66560724 |
missense |
probably benign |
0.00 |
R8214:Tg
|
UTSW |
15 |
66645247 |
missense |
probably damaging |
1.00 |
R8304:Tg
|
UTSW |
15 |
66565109 |
nonsense |
probably null |
|
R8688:Tg
|
UTSW |
15 |
66566802 |
critical splice donor site |
probably benign |
|
R8709:Tg
|
UTSW |
15 |
66553786 |
missense |
probably benign |
0.08 |
R8714:Tg
|
UTSW |
15 |
66555891 |
missense |
probably damaging |
0.97 |
R8901:Tg
|
UTSW |
15 |
66557184 |
missense |
probably damaging |
1.00 |
R8917:Tg
|
UTSW |
15 |
66645332 |
critical splice donor site |
probably null |
|
R9023:Tg
|
UTSW |
15 |
66555522 |
missense |
probably damaging |
1.00 |
R9232:Tg
|
UTSW |
15 |
66570310 |
missense |
probably benign |
0.01 |
R9310:Tg
|
UTSW |
15 |
66699118 |
missense |
possibly damaging |
0.69 |
R9361:Tg
|
UTSW |
15 |
66557246 |
missense |
possibly damaging |
0.50 |
R9389:Tg
|
UTSW |
15 |
66561173 |
missense |
probably benign |
0.04 |
R9501:Tg
|
UTSW |
15 |
66718923 |
missense |
possibly damaging |
0.52 |
R9510:Tg
|
UTSW |
15 |
66545913 |
missense |
probably damaging |
1.00 |
R9594:Tg
|
UTSW |
15 |
66607109 |
nonsense |
probably null |
|
R9629:Tg
|
UTSW |
15 |
66555587 |
missense |
possibly damaging |
0.95 |
R9701:Tg
|
UTSW |
15 |
66637991 |
missense |
probably benign |
0.03 |
R9743:Tg
|
UTSW |
15 |
66561839 |
missense |
probably benign |
0.18 |
R9748:Tg
|
UTSW |
15 |
66719008 |
missense |
possibly damaging |
0.91 |
T0975:Tg
|
UTSW |
15 |
66560712 |
missense |
probably benign |
0.01 |
X0005:Tg
|
UTSW |
15 |
66560712 |
missense |
probably benign |
0.01 |
X0065:Tg
|
UTSW |
15 |
66554303 |
missense |
probably damaging |
1.00 |
X0067:Tg
|
UTSW |
15 |
66620592 |
missense |
probably benign |
0.10 |
Z1177:Tg
|
UTSW |
15 |
66721396 |
missense |
probably benign |
0.02 |
Z1177:Tg
|
UTSW |
15 |
66557159 |
missense |
possibly damaging |
0.49 |
|
Mode of Inheritance |
Unknown |
Local Stock | |
Repository | |
Last Updated |
2019-09-04 9:30 PM
by Anne Murray
|
Record Created |
2019-01-23 10:19 AM
by Bruce Beutler
|
Record Posted |
2019-02-01 |
Phenotypic Description |
The samarai phenotype was identified among G3 mice of the pedigree R4797, some of which showed fasting hyperglycemia (Figure 1), reduced body weights (Figure 2), and increased total IgE levels in the serum (Figure 3) compared to wild-type littermates. Some mice also showed increased frequencies of B1a cells (Figure 4), CD44+ T cells (Figure 5), CD44+ CD4 T cells (Figure 6), CD44+ CD8 T cells (Figure 7), central memory CD4 T cells in CD4 T cells (Figure 8), and macrophages (Figure 9) with concomitant reduced frequencies of B2 cells (Figure 10) and IgM+ B cells (Figure 11), all in the peripheral blood.
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Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 65 mutations. All of the above anomalies were linked to mutations in two genes on chromosome 15: Efr3a and Tg. The mutation in Tg was presumed causative as the immune phenotype mimicked that of other mutant Tg alleles. The mutation in Tg is a G to A transition at base pair 66,758,006 (v38) on chromosome 15, or base pair 87,253 in the GenBank genomic region NC_000081 within the donor splice site of intron 36 (1-base pair from exon 36 [out of 48 total exons]). The strongest association was found with a recessive model of inheritance to the fasting glucose phenotype, wherein one variant homozygote departed phenotypically from four homozygous reference mice and nine heterozygous mice with a P value of 1.842 x 10-5 (Figure 12). The effect of the mutation at the cDNA and protein levels has not been examined, but the mutation is predicted to result in skipping of the 135-base pair exon 36. The mutation would cause an in-frame deletion of 45 amino acids after amino acid 2,085; the wild-type protein is normally 2,766 amino acids in length.
<--exon 35 <--exon 36 intron 36--> exon 37-->
6266 ……ACTGAGGAGAAGG ……TTCTGCTTACAGC gtaagggaatccctcag…… AATGTTCCCGT……
2082 ……-T--E--E--K-- ……-F--C--L--Q-- Q--C--S--R-……
correct deleted correct
|
The donor splice site of intron 36, which is destroyed by the samarai mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
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Illustration of Mutations in
Gene & Protein |
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Protein Prediction |
Tg encodes thyroglobulin (Tg), a precursor of two thyroid hormones: 3,5,3’ triiodothyronine (T3) and 3,5,3’,5’ tetraiodothyronine (thyroxine; T4). Tg has a 20-amino acid signal peptide (amino acids 1-20). The remaining Tg protein is comprised of 11 type 1, three type 2, three type 3a, and two type 3b Cys-rich repeats followed by an acetylcholinesterase (AChE)-like domain (Figure 13) (1-3). Tg can be divided into distinct regions: region I contains the ten type I repeats between amino acids 32 and 1211 along with linker and hinge segments; region II-III contains the type 2 repeats, the type I repeat at amino acids 1510-1564, and the type 3 repeats; and the AchE-like domain (amino acids 2181-2717) (4). Within the secretory system, Tg undergoes several posttranslational modifications including glycosylation, sialylation, sulfation, phosphorylation, iodination, and formation of approximately 60 intrachain disulfide binds per monomer. Upon reaching the follicular lumen, several tyrosines are iodinated. Several of the iodinated tyrosines are coupled to form T3and T4. The release of thyroid hormone occurs after several steps including intra-and extracellular proteolytic degradation of Tg by several proteases. The samarai mutation is predicted to result in a deletion of exon 16, which encodes amino acids 2,086 to 2,130. For more information about Tg, please see the record for ito.
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Putative Mechanism | Within the thyroid gland, epithelial cells synthesize thyroid hormones and are arranged as thyroid follicles. Between the thyroid follicles are parafollicular (alternatively, C cells), which secrete the hormone calcitonin. Tg is secreted by the thyroid cell into the follicular lumen by regulated (nonconstitutive), merocrine secretion. Upon stimulation by thyroid-stimulating hormone (TSH), Tg is reabsorbed by endocytosis/pinocytosis or phagocytosis (rodents only) to form endocytic/pinocytic vesicles or phagosomes, respectively. After release into the blood stream, T3 and T4 control metabolism. Mutations in TG have been linked to congenital goiter with hypothyroidism (euthyroidism) (OMIM: #274700) (5-7) as well as endemic and euthyroid nonendemic simple goiter (8-10). The 8q24 locus, which contains TG, is linked to autoimmune thyroid disease (AITD) including Graves’ disease and Hashimoto’s thyroiditis. Sequence analysis determined that TG is a AITD susceptibility gene in both humans and mice (11) (OMIM: #608175). The cog/cog (Tgcog; MGI:1856829) mouse model has a point mutation in Tg that causes a Leu to Pro substitution at amino acid 2263 (12;13). The cog/cog mouse exhibits congenital hypothyroidism with goiter as well as abnormal growth, mild anemia, and defects in central nervous system development (e.g., microcephalic cerebrum with hypomyelination) (14;15). Tg expression is normal in the cog/cog mice, but the Tg protein exhibits increased proteolysis (16;17). Furthermore, the Tgcog/cog protein exhibited abnormal folding, dimerication, and export as well increased levels of several ER molecular chaperones, all of which are indicative of an ER storage defect (18). As a result, the levels of total serum T4 and T3 are low with a concomitant increase in serum TSH levels (15). A second mouse model has an ENU-induced mutation in Tg (TgR1471X; MGI:5694939). The TgR1471X mice exhibited stunted growth (19). The samarai phenotype indicates that Tg function is impaired.
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Primers |
PCR Primer
samarai_pcr_F: CTCTTGCAGTAGTCTTCCACAG
samarai_pcr_R: AACTAACTGTAGAGCGCCCAG
Sequencing Primer
samarai_seq_F: CTATTCCTGGTGCTAACTATATGTGG
samarai_seq_R: TGTAGAGCGCCCAGTGAGG
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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 401 nucleotides is amplified (chromosome 15, + strand):
1 ctcttgcagt agtcttccac agtcttcatt ctattcctgg tgctaactat atgtggttgt 61 cccctgtttt gtctctcagt tacttcggac tcttggcaga ccctggccct gtcttcagtg 121 attgtagatc catccatcaa gcactttgat gttgcccaca tcagcactgc agccaccagt 181 aacttctcca tggcccaaga cttctgctta cagcgtaagg gaatccctca gagagagaga 241 gagagagtat ggcagggtct tagccaagta ctgccctgtg cagcaaccaa agacagacag 301 gagattcaat atggccttgg agtacctgac aggaaactac taacagagaa gggaagacat 361 aagactctct ccactcctca ctgggcgctc tacagttagt t
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References |
3. Swillens, S., Ludgate, M., Mercken, L., Dumont, J. E., and Vassart, G. (1986) Analysis of Sequence and Structure Homologies between Thyroglobulin and Acetylcholinesterase: Possible Functional and Clinical Significance. Biochem Biophys Res Commun. 137, 142-148.
5. Ieiri, T., Cochaux, P., Targovnik, H. M., Suzuki, M., Shimoda, S., Perret, J., and Vassart, G. (1991) A 3' Splice Site Mutation in the Thyroglobulin Gene Responsible for Congenital Goiter with Hypothyroidism. J Clin Invest. 88, 1901-1905.
8. Corral, J., Martin, C., Perez, R., Sanchez, I., Mories, M. T., San Millan, J. L., Miralles, J. M., and Gonzalez-Sarmiento, R. (1993) Thyroglobulin Gene Point Mutation Associated with Non-Endemic Simple Goitre. Lancet. 341, 462-464.
9. Perez-Centeno, C., Gonzalez-Sarmiento, R., Mories, M. T., Corrales, J. J., and Miralles-Garcia, J. M. (1996) Thyroglobulin Exon 10 Gene Point Mutation in a Patient with Endemic Goiter. Thyroid. 6, 423-427.
10. Gonzalez-Sarmiento, R., Corral, J., Mories, M. T., Corrales, J. J., Miguel-Velado, E., and Miralles-Garcia, J. M. (2001) Monoallelic Deletion in the 5' Region of the Thyroglobulin Gene as a Cause of Sporadic Nonendemic Simple Goiter. Thyroid. 11, 789-793.
11. Ban, Y., Greenberg, D. A., Concepcion, E., Skrabanek, L., Villanueva, R., and Tomer, Y. (2003) Amino Acid Substitutions in the Thyroglobulin Gene are Associated with Susceptibility to Human and Murine Autoimmune Thyroid Disease. Proc Natl Acad Sci U S A. 100, 15119-15124.
12. Kim, P. S., Hossain, S. A., Park, Y. N., Lee, I., Yoo, S. E., and Arvan, P. (1998) A Single Amino Acid Change in the Acetylcholinesterase-Like Domain of Thyroglobulin Causes Congenital Goiter with Hypothyroidism in the cog/cog Mouse: A Model of Human Endoplasmic Reticulum Storage Diseases. Proc Natl Acad Sci U S A. 95, 9909-9913.
19. Andrews, T. D., Whittle, B., Field, M. A., Balakishnan, B., Zhang, Y., Shao, Y., Cho, V., Kirk, M., Singh, M., Xia, Y., Hager, J., Winslade, S., Sjollema, G., Beutler, B., Enders, A., and Goodnow, C. C. (2012) Massively Parallel Sequencing of the Mouse Exome to Accurately Identify Rare, Induced Mutations: An Immediate Source for Thousands of New Mouse Models. Open Biol. 2, 120061.
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Science Writers | Anne Murray |
Illustrators | Diantha La Vine |
Authors | Jin Huk Choi, Xue Zhong, Takuma Misawa, Jeff SoRelle, Tao Yue, Zhao Zhang, and Bruce Beutler |