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Complex rearrangement in TBC1D4 in an individual with diabetes due to severe insulin resistance syndrome.

Authors
  • Cahn, Avivit1, 2
  • Mor-Shaked, Hagar1, 3
  • Rosenberg-Fogler, Hallel1, 3
  • Pollack, Rena1, 2
  • Tolhuis, Bas4
  • Sharma, Gaurav5
  • Schultz, Eric5
  • Yanovsky-Dagan, Shira3
  • Harel, Tamar6, 7
  • 1 Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. , (Israel)
  • 2 Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel. , (Israel)
  • 3 Department of Genetics, Hadassah Medical Center, Jerusalem, Israel. , (Israel)
  • 4 Pacific Bioscience, London, UK.
  • 5 Ocean Genomics, Pittsburgh, PA, USA.
  • 6 Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. [email protected]. , (Israel)
  • 7 Department of Genetics, Hadassah Medical Center, Jerusalem, Israel. [email protected]. , (Israel)
Type
Published Article
Journal
European Journal of Human Genetics
Publisher
Springer Nature
Publication Date
Feb 01, 2024
Volume
32
Issue
2
Pages
232–237
Identifiers
DOI: 10.1038/s41431-023-01512-8
PMID: 38086948
Source
Medline
Language
English
License
Unknown

Abstract

Severe insulin resistance syndromes result from primary insulin signaling defects, adipose tissue abnormalities or other complex syndromes. Mutations in TBC1D4 lead to partial insulin signaling defects, characterized mainly by postprandial insulin resistance. We describe an individual with severe insulin-resistant diabetes unresponsive to multiple therapies, in whom exome and genome analyses identified a complex rearrangement in TBC1D4. The rearrangement was of the pattern DUP-TRP/INV-DUP, with mutational signatures suggestive of replicative repair and Alu-Alu recombination as the underlying mechanisms. TBC1D4 encodes the TBC1D4/AS160 RabGTPase activating protein (RabGAP) involved in the translocation of glucose transporter 4 (GLUT4) from the cytosol to the cell membrane. Although the precise functional mechanism underlying insulin resistance in the proband is yet to be determined, this case provides further support for the link between TBC1D4 and hereditary insulin-resistant diabetes. © 2023. The Author(s), under exclusive licence to European Society of Human Genetics.

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