2. Academic Validation
  3. The actin and microtubule network regulator WHAMM is identified as a key kidney disease risk gene

The actin and microtubule network regulator WHAMM is identified as a key kidney disease risk gene

  • Cell Rep. 2025 Apr 22;44(4):115462. doi: 10.1016/j.celrep.2025.115462.
Dhanunjay Mukhi 1,  Lakshmi Prasanna Kolligundla 1,  Tomohito Doke 2,  Magaiver Andrade- Silva 3,  Hongbo Liu 4,  Matthew Palmer 5,  Katalin Susztak 6
Affiliations

Affiliations

  • 1 Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, PA, USA; Department of Nephrology, Nagoya University, Nagoya, Japan.
  • 3 Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, PA, USA; Department of Immunology, University of São Paulo, São Paulo, Brazil.
  • 4 Department of Biomedical Genetics, University of Rochester, Rochester, NY, USA.
  • 5 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 6 Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: ksusztak@pennmedicine.upenn.edu.
PMID: 40138314 DOI: 10.1016/j.celrep.2025.115462
Abstract

Nearly 850 million people suffer from kidney disease worldwide. Genome-wide association studies identify genetic variations at more than 800 loci associated with kidney dysfunction; however, the target genes, cell types, and mechanisms remain poorly understood. Here, we show that nucleotide variants on chromosome 15 are not only associated with kidney dysfunction but also regulate the expression of Wasp homolog associated with actin, membranes, and microtubules (WHAMM). WHAMM expression is higher in mice and patients with chronic and acute kidney disease. Mice with genetic deletion of Whamm appear healthy at baseline but develop less injury following cisplatin, folic acid, and unilateral ureteral obstruction. In vitro cell studies indicate that WHAMM controls cell death by regulating actin-mediated cytochrome c release from mitochondria and the formation of ASC speck. Pharmacological inhibition of actin dynamics mitigates kidney disease in experimental models. In summary, our study identifies a key role of WHAMM in the development of kidney disease.

Keywords

AKI; CKD; CP: Cell biology; GWAS; WASP family; WHAMM; actin cytoskeleton; autophagy; cell death; kidney tubules.

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