Characterization of novel pathogenic variants in RRAGD in autosomal dominant kidney tubulopathy and therapeutic perspectives

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Introduction
Variants in the Ras-related GTPase D (RRAGD) have been associated with autosomal dominant kidney hypomagnesemia (ADKH) characterized by hypokalemia, nephrocalcinosis, and dilated cardiomyopathy. RRAGD, which encodes for RagD protein, is involved in the activation of the mechanistic target of rapamycin complex 1 (mTORC1). Due to the limited characterization of patients’ phenotypes, the understanding of ADKH-RRAGD remains incomplete. Consequently, available treatment strategies are primarily symptomatic and insufficient. and
Methods
In the present case series, 12 new patients and 3 novel RRAGD variants, i.e. p.(Ser77Phe), p.(Thr91Ile), and p.(Ile100Arg), are described. To assess the pathogenicity of the novel variants, an in vitro assay of mTORC1 activity was performed. Additionally, the clinical response to diuretics (furosemide (n=4) and thiazide, n=4) and SGLT2 inhibitor dapagliflozin (n=6) was evaluated in patients carrying the RRAGD p.(Thr97Pro) variant during routine.
Results
The patients presented with kidney tubulopathies, including hypomagnesemia, hypercalciuria, and nephrocalcinosis. Four patients also exhibited dilated cardiomyopathy. In vitro assays demonstrated constitutive activation of non-canonical mTORC1 signaling caused by the p.(Ser77Phe) and p.(Ile100Arg) variants. Clinically, patients remained sensitive to diuretic challenges, while dapagliflozin treatment increased serum magnesium (Mg²⁺) levels by 0.04 mM but exacerbated hypokalemia.
Conclusion
To date, 36 patients with ADKH-RRAGD have been identified. Kidney tubulopathy is the most prominent feature within the phenotypic spectrum of ADKH-RRAGD. Molecularly, constitutive activation of non-canonical mTORC1 is present in most RRAGD variants. From a therapeutic perspective, dapagliflozin may increase serum Mg2+ levels in patients with RRAGD variants.