Basement membrane defects in CD151-associated glomerular disease

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• CD151, a tetraspanin family member, is crucial for podocyte adhesion to the glomerular basement membrane (GBM) via interaction with integrin ɑ3β1.
• Mouse models lacking Cd151 exhibit glomerular dysfunction, including proteinuria and focal glomerulosclerosis.
• CD151 is not routinely screened in patients with nephrotic-range proteinuria, necessitating further investigation into its role in human kidney disease.

Observation:

• A child with nail dystrophy and recurrent urinary tract infections presented with nephrotic-range proteinuria.
• Targeted next-generation sequencing (NGS) identified a novel, homozygous truncating variant in the CD151 gene.
• Kidney biopsy revealed GBM thickening and podocyte effacement, with reduced CD151 expression.

Findings:

• The identified CD151 variant was confirmed as disease-causing using CRISPR-Cas9 in zebrafish, where cd151 depletion induced proteinuria.
• The zebrafish proteinuria model was rescued by wild-type CD151 mRNA, but not by the variant mRNA.
• Patient red blood cells showed no immunoreactivity to anti-CD151/MER2 antibodies, consistent with the genetic findings.

Implications:

• This study identifies a novel CD151 variant associated with nephrotic-range proteinuria and microscopic hematuria in a pediatric patient.
• It provides further evidence for CD151's critical role in glomerular disease pathogenesis.
• The findings underscore the importance of considering CD151 in the genetic workup of unexplained nephrotic syndrome and highlight a pipeline for functional variant analysis.