Aberrant serum-derived FN1 variants bind to integrin β1 on glomerular endothelial cells contributing to thin basement...

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• The glomerular basement membrane (GBM) is vital for kidney filtration, and its thickness impacts renal function.
• Thin basement membrane nephropathy (TBMN) is characterized by a uniformly thinned GBM, causing hematuria but often preserving normal renal function.
• The underlying causes and progression of TBMN remain incompletely understood.

Purpose of the Study:

• To investigate the genetic basis of TBMN in patients with microscopic hematuria.
• To elucidate the molecular mechanisms by which genetic variants lead to TBMN.
• To identify novel therapeutic targets and differentiate TBMN from other kidney diseases.

Main Methods:

• Analysis of clinical cohorts with microscopic hematuria undergoing genetic testing.
• Identification and bioinformatics analysis of novel pathogenic FN1 mutations.
• Expression localization studies in renal biopsies and functional analysis of mutant proteins.

Main Results:

• Five novel pathogenic FN1 mutations were identified in patients with TBMN.
• These FN1 variants demonstrated gain-of-function characteristics, leading to aberrant serum-derived FN1 deposition.
• Excessive FN1 deposition disrupted Integrin β1 and Laminin α5β2γ1 interactions, reducing key GBM components and causing TBMN.

Conclusions:

• This study reveals the genetic pathogenesis of TBMN driven by FN1 variants for the first time.
• The findings provide a basis for understanding renal dysfunction progression in hematuria patients.
• This research offers potential for targeted therapies and distinguishes TBMN from early Alport syndrome.