KIRREL1 and Steroid-resistant Nephrotic Syndrome

This summary details the association between KIRREL1 and steroid-resistant nephrotic syndrome. The evidence is derived from multi‐patient genetic studies, which have identified pathogenic homozygous variants in KIRREL1 among affected individuals with progressive kidney disease, establishing an important gene-disease link (PMID:31472902). The consistency of the phenotype, namely chronic kidney disease progressing to end-stage renal failure, supports the clinical relevance of this association.

Genetic evidence from two unrelated families revealed homozygous missense mutations in KIRREL1. A key variant, selected for its clear HGVS notation, is c.1718C>T (p.Ser573Leu). This variant was found segregating with the disease in the affected families, underlining the autosomal recessive inheritance pattern of the disorder (PMID:31472902). The identification of this mutation provides robust support for variant pathogenicity.

The observed inheritance mode in the described families is autosomal recessive, with the affected individuals demonstrating homozygosity for the mutation. Although explicit counts of additional affected relatives were not provided, the segregation pattern within these families further bolsters the genetic association and aids diagnostic evaluation.

Functional studies have contributed significantly to understanding the mechanism of pathogenicity. In vitro analyses demonstrated that mutant KIRREL1 proteins, including those with the c.1718C>T (p.Ser573Leu) variant, fail to localize properly at the podocyte cell membrane. This mislocalization disrupts the formation of the slit diaphragm, a vital component of the glomerular filtration barrier, thereby linking the genetic alteration to the disease phenotype (PMID:31472902).

Integrating the genetic and functional evidence provides a cohesive narrative that supports a strong role for KIRREL1 in the pathogenesis of steroid-resistant nephrotic syndrome. The convergence of molecular data and experimental validation underscores the clinical utility of screening for KIRREL1 variants in patients with a compatible phenotype. These findings not only facilitate diagnostic decision-making but also offer potential avenues for targeted therapeutic intervention.

Key take‐home message: The robust association between homozygous KIRREL1 mutations, particularly c.1718C>T (p.Ser573Leu), and steroid-resistant nephrotic syndrome underscores its importance in clinical diagnostics and presents a clear target for future research into disease mechanisms and treatment strategies.

References

• Kidney International • 2019 • Mutations in KIRREL1, a slit diaphragm component, cause steroid‑resistant nephrotic syndrome PMID:31472902
• Human Molecular Genetics • 2010 • A model organism approach: defining the role of Neph proteins as regulators of neuron and kidney morphogenesis PMID:20233749

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