A mutation in Tpst2 encoding tyrosylprotein sulfotransferase causes dwarfism associated with hypothyroidism.

Abstract

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.

• Authors: Nobuya Sasaki, Yayoi Hosoda, Aogu Nagata, Ming Ding, Ji-Ming Cheng, Tomomi Miyamoto, Shinya Okano, Atsushi Asano, Ichiro Miyoshi, Takashi Agui
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 21 Issue 7 Pg. 1713-21 (Jul 2007) ISSN: 0888-8809 [Print] United States
• PMID: 17456791 (Publication Type: Journal Article)

Chemical References

• DNA Primers
• Receptors, Thyrotropin
• Thyrotropin
• Sulfotransferases
• protein-tyrosine sulfotransferase

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Congenital Hypothyroidism (complications, enzymology, genetics)
• DNA Primers (genetics)
• Dwarfism (complications, enzymology, genetics)
• Female
• Genetic Complementation Test
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mice, Transgenic
• Molecular Sequence Data
• Mutation, Missense
• Phenotype
• Protein Processing, Post-Translational
• Receptors, Thyrotropin (metabolism)
• Sequence Homology, Amino Acid
• Signal Transduction
• Substrate Specificity
• Sulfotransferases (deficiency, genetics, metabolism)
• Thyrotropin (metabolism)