Phenotypic Mutation 'sariba' (pdf version)
Allele | sariba |
Mutation Type |
missense
|
Chromosome | 15 |
Coordinate | 66,566,719 bp (GRCm39) |
Base Change | A ⇒ G (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 |
Serine changed to Glycine
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000070239]
|
AlphaFold |
no structure available at present |
SMART Domains |
Protein: ENSMUSP00000070239 Gene: ENSMUSG00000053469 AA Change: S1256G
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 benign
PolyPhen 2
Score 0.010 (Sensitivity: 0.96; Specificity: 0.77)
(Using ENSMUST00000065916)
|
Meta Mutation Damage Score |
0.0941 |
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 |
samarai
|
UTSW |
15 |
66629855 |
critical splice donor site |
probably null |
|
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
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Record Created |
2019-01-23 10:17 AM
by Bruce Beutler
|
Record Posted |
2019-02-01 |
Phenotypic Description |
The sariba phenotype was identified among G3 mice of the pedigree R0135, some of which showed increased frequencies of CD44+ T cells in the peripheral blood (Figure 1).
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Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 79 mutations. The CD44+ T cell phenotype was linked to mutations in three genes on chromosome 15: Tg, Mei1, and Pnpla5. The mutation in Tg was presumed causative as the immune phenotype mimicked that of other mutant Tg alleles. The mutation in Tg is an A to G transition at base pair 66,694,870 (v38) on chromosome 15, or base pair 24,117 in the GenBank genomic region NC_000081 encoding Tg. Linkage was found with a recessive model of inheritance, wherein three variant homozygotes departed phenotypically from three homozygous reference mice and five heterozygous mice with a P value of 0.000489 (Figure 2). The mutation corresponds to residue 3,788 in the NM_009375 mRNA sequence in exon 5 of 48 total exons.
3773 CGCCAGGGCCTCCGGAGTGCGTTTTCACCAGGG
1251 -R--Q--G--L--R--S--A--F--S--P--G-
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The mutated nucleotide is indicated in red. The mutation results in a serine to glycine substitution of position 1,256 (S1256G) in the thyroglobulin protein, and is strongly predicted by PolyPhen-2 to be benign (score = 0.010).
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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 3) (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 sariba mutation results in a serine to glycine substitution of position 1,256 (S1256G) within an undefined region between the tenth type 1 Cys-rich repeat and the first type 2 Cys-rich repeat. 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 sariba phenotype indicates that Tg function is impaired. Expression and localization of Tgsariba has not been examined.
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Primers |
PCR Primer
sariba_pcr_F: CTGCCTGTCTGGTGAAACTGAGAG
sariba_pcr_R: ACCTGACGTGAAAAGGCTGTACTTG
Sequencing Primer
sariba_seq_F: CTGAGAGACAGTGGACTTATCC
sariba_seq_R: CTTGAGTGGCAGGAAGTCTCTAAC
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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 495 nucleotides is amplified (chromosome 15, + strand):
1 ctgcctgtct ggtgaaactg agagacagtg gacttatcca gtgaggagtc atagaaggag 61 ggaaaagaac taggccctga cagagcagga cacaatgaga aagggcttgg ggaacaatca 121 agggaagcag atgggtaggc agagctgggt ttaagtctgg gaggtaccca tgcctcttct 181 ccatcgctgc tcctaggccc acagtgtcca ctgccattct ctgggtcaga tgtggctgat 241 ggagtgatct tctgcgagac agcctctagc tcaggagtga cgactgttca gcagtgccag 301 ctgctgtgcc gccagggcct ccggagtgcg ttttcaccag ggccactgat ttgtagcctg 361 gagagtcagc actgggtgac actgccacca ccccgagcct gtcaaagtga gtagcactgg 421 ggagactcat ccttcactct cagggctatt gttagagact tcctgccact caagtacagc 481 cttttcacgt caggt
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, and Bruce Beutler |