RGD Reference Report - A novel missense mutation (G2320R) in thyroglobulin causes hypothyroidism in rdw rats. - Rat Genome Database

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A novel missense mutation (G2320R) in thyroglobulin causes hypothyroidism in rdw rats.

Authors: Hishinuma, A  Furudate, S  Oh-Ishi, M  Nagakubo, N  Namatame, T  Ieiri, T 
Citation: Hishinuma A, etal., Endocrinology 2000 Nov;141(11):4050-5.
RGD ID: 730133
Pubmed: PMID:11089535   (View Abstract at PubMed)
DOI: DOI:10.1210/endo.141.11.7794   (Journal Full-text)

The rdw rat is a hereditary hypothyroid variant initially derived from the Wistar-Imamichi strain. Proteome analysis by two-dimensional gelelectrophoresis showed that molecular chaperones accumulated in the thyroid glands, suggesting retention of abnormal proteins in the endoplasmic reticulum (ER). Anatomical studies indicated that thyroglobulin (Tg) was not secreted into the follicular lumina, but retained in the dilated ER. Sequencing of the entire Tg complementary DNA from the rdw rat revealed a missense mutation (G2320R) in the acetylcholinesterase-like domain at the 2320th amino acid residue. Carbohydrate residues of the G2320R Tg mutant were of the high-mannose ER type, as shown by sensitivity to the treatment with endoglycosidase H. Molecular chaperones, GRP94, GRP78, and calreticulin, were all accumulated in the rdw rat thyroid glands. Computer analysis of protein secondary structure predicted that the mutation would cause extension of the helix where beta-sheet and turns were formed in the normal Tg. Altered folding of Tg might account for the impaired intracellular transport of Tg and activated premature degradation by the same mechanism as in ER storage diseases.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hypothyroidism  ISOTg (Rattus norvegicus)730133; 730133DNA:missense mutation:CDS:p.G2320R (rat)RGD 
hypothyroidism  IAGP 730133DNA:missense mutation:CDS:p.G2320R (rat)RGD 
hypothyroidism  IAGP 730133; 730133compared to wild type and heterozygotesRGD 
isolated growth hormone deficiency  ISOTg (Rattus norvegicus)730133; 730133 RGD 
isolated growth hormone deficiency  IAGP 730133; 730133; 730133 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal endoplasmic reticulum morphology  IAGP 730133DNA:missense mutation:cds:p.G2320R ratRGD 
abnormal endoplasmic reticulum morphology  IAGP 730133; 730133compared to wild type and heterozygotesRGD 
decreased body weight  IAGP 730133DNA:missense mutation:cds:p.G2320R ratRGD 
decreased body weight  IAGP 730133; 730133compared to wild type and heterozygotesRGD 
increased endoplasmic reticulum stress  IAGP 730133DNA:missense mutation:cds:p.G2320R ratRGD 
increased endoplasmic reticulum stress  IAGP 730133; 730133compared to wild type and heterozygotesRGD 
small adenohypophysis  IAGP 730133; 730133; 730133 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Tg  (thyroglobulin)
Tgrdw  (thyroglobulin; rdw mutant)

Genes (Mus musculus)
Tg  (thyroglobulin)

Genes (Homo sapiens)
TG  (thyroglobulin)

Strains
WIC-Tgrdw/Kts  (NA)

Objects referenced in this article
Strain F344.WIC-TgrdwKts null Rattus norvegicus

Additional Information