ARHGDIA – Steroid‑Resistant Nephrotic Syndrome

Multiple independent studies support a strong association between pathogenic variants in ARHGDIA and steroid‑resistant nephrotic syndrome (SRNS). Targeted gene panel analyses in South Indian children identified a pathogenic ARHGDIA variant in 2 patients (PMID:30458709), while an Iranian cohort study also reported a disease‑causing variant in a single case among 30 families (PMID:36245711). Familial segregation data, with 19 additional affected relatives demonstrating co‑segregation of the variant, further underscore the autosomal recessive inheritance of this condition (PMID:30458709).

Genetic evidence is exemplified by the identification of a truncating mutation, c.358C>T (p.Arg120Ter), in ARHGDIA. This variant, along with others observed across independent cohorts, supports a loss‑of‑function mechanism that disrupts the normal regulation of RHO GTPase signaling. Although one study evaluating heterozygous variants reported similar frequencies in controls (PMID:39127776), the overall weight of genetic evidence favors a pathogenic role when mutations occur in a biallelic context.

Functional studies provide robust support for the role of ARHGDIA in podocyte biology. Detailed experiments demonstrated that ARHGDIA mutations increase active RAC1 and CDC42 levels, leading to aberrant podocyte migration. These findings were recapitulated in arhgdia‑deficient zebrafish models, where treatment with RAC1 inhibitors partially ameliorated the nephrotic phenotype (PMID:23867502).

The convergent evidence from both genetic and experimental studies strongly endorses the pathogenicity of loss‑of‑function mutations in ARHGDIA within the context of SRNS. Despite conflicting reports regarding the significance of heterozygous variants, the data clearly indicate that biallelic, truncating changes underlie the disease mechanism.

In summary, the combined genetic and functional findings not only enhance our understanding of ARHGDIA’s role in SRNS but also support its inclusion in diagnostic gene panels, particularly in populations with high rates of consanguinity. This integrated evidence is critical for clinical decision‑making and the development of targeted therapeutic strategies.

Key Take‑home sentence: The strong genetic and functional evidence for ARHGDIA loss‑of‑function mutations solidifies its clinical utility as a diagnostic marker for steroid‑resistant nephrotic syndrome.

References

• BMC Medical Genetics • 2018 • Targeted gene panel for genetic testing of south Indian children with steroid resistant nephrotic syndrome PMID:30458709
• Frontiers in Pediatrics • 2022 • High detection rate for disease‑causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases PMID:36245711
• Scientific Reports • 2024 • Rare heterozygous variants in paediatric steroid resistant nephrotic syndrome - a population‑based analysis of their significance PMID:39127776
• The Journal of Clinical Investigation • 2013 • ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling PMID:23867502

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