Functional characterization of a novel TSH receptor mutation (V711fs) with protein instability

2014 Fiscal Year Final Research Report

• Project/Area Number: 24791087
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Keio University
• Principal Investigator: NARUMI Satoshi 慶應義塾大学, 医学部, 特任助教 (40365317)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 先天性甲状腺機能低下症 / TSH受容体 / 変異 / たんぱく質不安定性 / プロテアソーム

Outline of Final Research Achievements

We analyzed a TSH receptor mutation V711FfsX18, which was observed in a patient with congenital hypothyroidism. This mutation was subject to proteasome-dependent protein degradation. Two models were considered as a explanation for the protein instability of the mutation: Model 1, Loss of intact 54 aa C-terminal sequence; Model 2, Acquisition of frame-shifted 17 aa sequence. The result of cAMP-generating activity of the V711X mutation, which was comparable to wildtype, excluded the Model 1. When the 17-aa sequence was fused to the green fluorescent protein or the luciferase protein, remarkable reduction in their activities were shown. Based on these observations, we concluded that acquisition of 17-aa frame-shifted sequence causes the protein instability of the V711FfsX TSH receotor mutation.

Free Research Field

小児内分泌学