Abstract: TH-PO0045
IQGAP1: A Novel Regulator of the Na-Cl Cotransporter (NCC) and a Candidate Gene for Gitelman-Like Syndromes
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Wan, Elizabeth Rose, University College London, London, England, United Kingdom
- Thines, Louise, National Institutes of Health, Bethesda, Maryland, United States
- Li, Zhigang, National Institutes of Health, Bethesda, Maryland, United States
- Sayedyahossein, Samar, National Institutes of Health, Bethesda, Maryland, United States
- Siew, Keith, University College London, London, England, United Kingdom
- Sacks, David, National Institutes of Health, Bethesda, Maryland, United States
- Marks, Joanne, University College London, London, England, United Kingdom
Background
The sodium chloride co-transporter (NCC) [SLC12A3], and its regulation by the CUL3/KLHL3-CAB39-WNK-SPAK/OxSR1 pathway, is the source of intense research focus due to their central role in electrolyte and blood pressure homeostasis. The study of families and animal models with defects in these genes have substantially advanced our understanding of renal electrolyte handling. Here we describe a patient and a complementary animal model with disruption of a novel candidate gene IQGAP1 resulting in a Gitelman-like phenotype.
Methods
The patient was referred for genetic and functional testing after presenting with hypomagnesemia, hypokalaemia, hypocalciuria, and hypotension. Molecular investigation of IQGAP1 function involved immunoblotting, co-immunoprecipitations and immunofluorescent staining of human/mouse kidneys. In vivo investigation of electrolyte homeostasis used an Iqgap1-null mouse model for the functional protein.
Results
A blunted thiazide response (ΔFECl 1.25%; normal: >2.3%) in the patient suggested loss of NCC function. Whole exome sequencing was negative for known causative genes (SLC12A3, CLCKNB) or interactors (WNK4, STK39, etc) but a filtering approach identified a homozygous 5 base-pair deletion in IQGAP1.
IQGAP1 co-immunoprecipitated with NCC and CAB39 in HEK293, mDCT209 & mDCT15 cell lines, and co-localised with NCC at the apical membrane of both human and mouse distal convoluted tubules.
Iqgap1-/- mice exhibited abnormal renal electrolyte handling of magnesium, calcium & chloride consistent with a Gitelman-like phenotype. Iqgap1-/- kidney immunoblots showed total NCC abundance is preserved, but immunostaining revealed loss of phosphorylation at critical residues needed for NCC activity.
Conclusion
IQGAP1, a large multi-domain protein involved in cytoskeleton regulation and cell signalling integration, directly interacts with NCC and modulates NCC phosphorylation.
Acknowledgment
We gratefully acknowledge the contribution of the late Professor Stephen B. Walsh, whose vision and foundational work were central to the inception of this project.
EW gratefully acknowledges the support of Kidney Research UK for this project through grant TF_007_20191202.
Figure 1: IQGAP1 and NCC co-localise in the distal convoluted tubule. In IQGAP1 -/- mice, NCC phospho-Thr58 staining is absent
Funding
- Other NIH Support