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

European Journal of Human Genetics volume 32, pages 232–237 (2024)Cite this article

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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.

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Fig. 1: Pedigree of affected individual.
Fig. 2: Clinical course of the patient.
Fig. 3: Complex rearrangement identified in TBC1D4.
Fig. 4: Breakpoint junctions.

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Data availability

Data generated in this study are found in the published article. Additional data are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank the patient for his participation in this study.

Funding

No specific funding sources to declare.

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Author notes

  1. These authors contributed equally: Avivit Cahn, Hagar Mor-Shaked.

Authors and Affiliations

  1. Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Avivit Cahn, Hagar Mor-Shaked, Hallel Rosenberg-Fogler, Rena Pollack & Tamar Harel

  2. Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel

    Avivit Cahn & Rena Pollack

  3. Department of Genetics, Hadassah Medical Center, Jerusalem, Israel

    Hagar Mor-Shaked, Hallel Rosenberg-Fogler, Shira Yanovsky-Dagan & Tamar Harel

  4. Pacific Bioscience, London, UK

    Bas Tolhuis

  5. Ocean Genomics, Pittsburgh, PA, USA

    Gaurav Sharma & Eric Schultz

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  1. Avivit Cahn
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Contributions

AC, HM-S and TH conceptualized the study and wrote the manuscript with input from all authors. AC and RP collected and analyzed clinical information. HM-S, BT, GS and ES analyzed genomic information. HR-F, SY-D and TH analyzed genomic data, and designed and performed molecular experiments.

Corresponding author

Correspondence to Tamar Harel.

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Competing interests

BT is an employee of Pacific Bioscience, GS and ES are employees of Ocean Genomics, and HM-S is an employee of Geneyx Genomix. The other authors declare no conflict of interest.

Ethics approval and consent for publication

The study was conducted in accordance with IRB-approved protocol 0306-10-HMO. Consent for publication was confirmed.

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Cahn, A., Mor-Shaked, H., Rosenberg-Fogler, H. et al. Complex rearrangement in TBC1D4 in an individual with diabetes due to severe insulin resistance syndrome. Eur J Hum Genet 32, 232–237 (2024). https://doi.org/10.1038/s41431-023-01512-8

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