title: A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia.
abstract: 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 insulin-resistant 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.
authors.affiliation: Departments of Medicine and Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Satya
authors.initials: S
authors.lastname: Dash
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sano
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Rochford
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.forename: Giles
authors.initials: G
authors.lastname: Yeo
authors.forename: Caroline S S
authors.initials: CS
authors.lastname: Hyden
authors.forename: Maria A
authors.initials: MA
authors.lastname: Soos
authors.forename: James
authors.initials: J
authors.lastname: Clark
authors.forename: Andrew
authors.initials: A
authors.lastname: Rodin
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.forename: Celine
authors.initials: C
authors.lastname: Druet
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fawcett
authors.forename: Y C Loraine
authors.initials: YC
authors.lastname: Tung
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: Gustav E
authors.initials: GE
authors.lastname: Lienhard
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
mesh_terms: D000052:Acanthosis Nigricans / Q000235:genetics*; D018389:Codon, Nonsense; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics*; D008297:Male; D010375:Pedigree; D017354:Point Mutation
chemical_list: D018389:Codon, Nonsense; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; C518767:TBC1D4 protein, human