Novel Truncating Variants in PODXL Represent a New Entity to Be Explored Among Podocytopathies

Area of Science:

• Genetics and Molecular Biology
• Nephrology
• Human Disease Pathogenesis

Background:

• Podocalyxin (PODXL) is a key sialoprotein in kidney podocytes, crucial for glomerular filtration and podocyte development.
• PODXL haploinsufficiency is implicated in focal segmental glomerulosclerosis (FSGS), a progressive kidney disease, but its full spectrum remains unclear.

Purpose of the Study:

• To investigate the role of truncating variants in the PODXL gene in adult-onset chronic kidney disease (CKD).
• To identify and characterize novel genetic variants associated with podocytopathy.

Main Methods:

• High-throughput sequencing was employed in a cohort of young adults diagnosed with CKD.
• Affected individuals with truncating variants in the PODXL gene were identified, and their families were tested for segregation of these variants.

Main Results:

• The PODXL gene showed characteristics consistent with dominant inheritance with variable expression or incomplete penetrance.
• Four new truncating variants in PODXL were discovered, alongside previously reported monoallelic variants.

Conclusions:

• The findings provide further evidence linking genetic defects in PODXL to a distinct molecular entity of adult-onset podocytopathy.
• Specific sequence features of PODXL necessitate careful variant interpretation to understand their functional impact.