A mutation in Tpst2 encoding tyrosylprotein sulfotransferase causes dwarfism associated with hypothyroidism.
The growth-retarded (grt) mouse has an autosomal recessive, fetal-onset, severe thyroid hypoplasia related to TSH hyporesponsiveness. Through genetic mapping and complementation experiments, we show that grt is a missense mutation of a highly conserved region of the tyrosylprotein sulfotransferase 2 (Tpst2) gene, encoding one of the two Tpst genes implicated in posttranslational tyrosine O-sulfation. We present evidence that the grt mutation leads to a loss of TPST2 activity, and TPST2 isoform has a high degree of substrate preference for TSH receptor (TSHR). The expression of TPST2 can restore TSH-TSHR-mediated cAMP production in fibroblasts derived from grt mice. Therefore, we propose that the tyrosine sulfation of TSHR by TPST2 is crucial for TSH signaling and resultant thyroid gland function.
Sasaki
Nobuya
N
Laboratory of Experimental Animal Science, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
Hosoda
Yayoi
Y
Nagata
Aogu
A
Ding
Ming
M
Cheng
Ji-Ming
JM
Miyamoto
Tomomi
T
Okano
Shinya
S
Asano
Atsushi
A
Miyoshi
Ichiro
I
Agui
Takashi
T
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003409:Congenital Hypothyroidism / Q000150:complications / Q000201:enzymology* / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D004392:Dwarfism / Q000150:complications / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D005816:Genetic Complementation Test; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D011989:Receptors, Thyrotropin / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013379:Substrate Specificity; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D013972:Thyrotropin / Q000378:metabolism
D017931:DNA Primers; D011989:Receptors, Thyrotropin; D013972:Thyrotropin; D015238:Sulfotransferases; C039079:protein-tyrosine sulfotransferase