A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia

作者：Dash Satya; Sano Hiroyuki; Rochford Justin J; Semple Robert K; Yeo Giles; Hyden Caroline S S; Soos Maria A; Clark James; Rodin Andrew; Langenberg Claudia; Druet Celine; Fawcett Katherine A; Tung Y C Loraine; Wareham Nicolas J; Barroso Ines; Lienhard Gustav E; O'Rahilly Stephen^*; Savage David B

来源：Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(23): 9350-9355.

DOI：10.1073/pnas.0900909106

• glucose transport
• insulin resistance
• AS160

Tre-2, BUB2, CDC16, 1 domain family member 4 (TBC1D4) (AS160) is a Rab-GTPase activating protein implicated in insulin-stimulated glucose transporter 4 (GLUT4) translocation in adipocytes and myotubes. To determine whether loss-of-function mutations in TBC1D4 might impair GLUT4 translocation and cause insulin resistance in humans, we screened the coding regions of this gene in 156 severely insulinresistant patients. A female presenting at age 11 years with acanthosis nigricans and extreme postprandial hyperinsulinemia was heterozygous for a premature stop mutation (R363X) in TBC1D4. After demonstrating reduced expression of wild-type TBC1D4 protein and expression of the truncated protein in lymphocytes from the proband, we further characterized the biological effects of the truncated protein in 3T3L1 adipocytes. Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels (P = 0.053) and significantly reduced insulin-stimulated GLUT4 cell membrane translocation (P < 0.05). When coexpressed with wild- type TBC1D4, the truncated protein dimerized with full-length TBC1D4, suggesting that the heterozygous truncated variant might interfere with its wild- type counterpart in a dominant negative fashion. Two overweight family members with the mutation also manifested normal fasting glucose and insulin levels but disproportionately elevated insulin levels following an oral glucose challenge. This family provides unique genetic evidence of TBC1D4 involvement in human insulin action.

• 出版日期2009-6-9