ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: SA-PO978

Podocytopathy with a Novel Variant in ARHGAP24 and an APOL1 Risk Allele

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Dalal, Vidhi, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
  • Lane, Jerome C., Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Introduction

Genetic mutations cause up to 30% of steroid resistant nephrotic syndrome (SRNS) cases. A missense mutation responsible for hereditary podocytopathy was first described in ARHGAP24, a gene that encodes a GTPase activating protein (GAP) required for regulating podocyte motility, in 2011. We report a case of SRNS with an ARHGAP24 variant that has not been previously reported to our knowledge and a concurrent APOL1 risk allele.

Case Description

A 16-month-old male presented with anasarca, nephrotic range proteinuria, hypoalbuminemia, hypertension, microscopic hematuria, and severe anemia. Infectious work-up (hepatitis, HIV, COVID) was negative, and serum complement levels were within normal limits. Renal biopsy showed severe podocytopathy. Genetic testing showed a G1 APOL1 risk allele and a heterozygous missense mutation (c.584 A>C; p.K195T) in ARHGAP24. After a lack of response on 8 weeks of high dose steroids, the patient was transitioned to tacrolimus.

Discussion

Our patient’s ARHGAP24 mutation is in the critical GAP domain that regulates podocyte motility. The ARHGAP24 mutation described in 2011 was also in the GAP domain, causing reduced GAP activity and increased podocyte motility with a dominant effect attributed to heterodimerization of the mutated and wildtype (WT) proteins. Our patient’s mutation replaces lysine (positively charged) with threonine (neutral). This lysine residue, per Alphafold, is predicted to form a cation-pi interaction with a tyrosine residue in the GAP domain of the WT protein. Lysine is also highly conserved at this position across species. Therefore, we hypothesize that the positively charged lysine residue is required for preserving the GAP domain’s integrity, and changing the residue to a neutral amino acid (threonine in our patient’s case) disrupts the GAP domain. Despite the genetic findings, we opted to treat with tacrolimus, as the pathogenicity of this variant has not been confirmed. The patient also has a G1 APOL1 risk allele – while 1 allele is not expected to confer the risk associated with having 2 APOL1 risk alleles, the combination of 1 risk allele with a possibly pathogenic mutation in another gene has not been well-described. Thus, our patient presents multiple genetic findings that require further investigation to define their contribution to his podocytopathy and to determine if and how the two gene variants interact with each other.