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Kidney Week

Abstract: SA-OR13

Whole-Genome Sequencing Identifies a Dominant Negative ADIPOQ Mutation in a Type 2 Diabetic Family Enriched for ESRD

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Pezzolesi, Marcus G., University of Utah Health Care, Department of Internal Medicine, Salt Lake City, UT, US, Salt Lake City, Utah, United States
  • Simeone, Christopher A., University of Utah Health Care, Department of Internal Medicine, Salt Lake City, UT, US, Salt Lake City, Utah, United States
  • Wilkerson, Joseph L., University of Utah Health Care, Department of Internal Medicine, Salt Lake City, UT, US, Salt Lake City, Utah, United States
  • Lazaro guevara, Jose M., University of Utah Health Care, Department of Internal Medicine, Salt Lake City, UT, US, Salt Lake City, Utah, United States
  • Hernandez, Edgar Javier, University of Utah Health Care, Department of Internal Medicine, Salt Lake City, UT, US, Salt Lake City, Utah, United States
  • Gorsi, Bushra, University of Utah Health Care, Department of Internal Medicine, Salt Lake City, UT, US, Salt Lake City, Utah, United States
  • Frodsham, Scott G., University of Utah Health Care, Department of Internal Medicine, Salt Lake City, UT, US, Salt Lake City, Utah, United States
  • O'Neil, Kristina V., Joslin Diabetes Center, Harvard Medical School, Boston, MA, US, Boston, Massachusetts, United States
  • Summers, Scott, University of Utah Health Care, Department of Internal Medicine, Salt Lake City, UT, US, Salt Lake City, Utah, United States
  • Krolewski, Andrzej S., Joslin Diabetes Center, Harvard Medical School, Boston, MA, US, Boston, Massachusetts, United States
  • Holland, William L., University of Utah Health Care, Department of Internal Medicine, Salt Lake City, UT, US, Salt Lake City, Utah, United States
Background

Diabetic nephropathy (DN) is a complex, heterogeneous complication of diabetes. Despite evidence of its strong genetic predisposition, identification of the genetic factors that contribute to DN and the risk of end-stage renal disease (ESRD) has been challenging.

Methods

We performed whole genome sequencing (WGS) in a multi-generational family enriched for both type 2 diabetes and ESRD followed by unified linkage analysis and rare variant association testing using pVAAST.

Results

Using WGS to evaluate this family, we identified a rare loss-of-function mutation in adiponectin (ADIPOQGly93GlufsTer73; seen only once among 56,810 non-Finnish Europeans included in the gnomAD database) observed among 6 ESRD cases in this family. This 10-nucleotide deletion results in a premature termination codon and a complete loss of adiponectin’s globular domain. We found that carriers of this mutation have low circulating adiponectin (15% of normal levels) and dramatically high ceramide levels (double the level of C16 ceramides as compared with ADIPOQwt diabetic patients). In cell culture, we observed that ADIPOQGly93GlufsTer73 is degraded by the proteasome. Likely due to its incorporation to trimeric adiponectin, over-expression of the mutant protein decreases stability of wildtype adiponectin and exerts a dominant-negative effect that results in reduced adiponectin levels.

Conclusion

Here we report the first human family with a dominant-negative mutation in adiponectin. Importantly, while adiponectin is known to play important roles in insulin sensitivity, it also has a protective role in mitigating renal injury in patients with diabetes. Moreover, adiponectin knockout mice are prone to DN and podocyte apoptosis. Together, these data provide strong evidence supporting the role of adiponectin in kidney disease in patients with diabetes.