Mosaic PKHD1 variants in polycystic kidney caused aberrant protein profiling of mitochondria and lysosomes

Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal cystic disease mainly caused by PKHD1. However, its genetic cause, pathological features, and mechanism remained unsolved. Here, we present a rare case in an ARPKD family that two siblings harboring biallelic variants in PKHD1. Exosome proteomic analysis and Immunohistochemistry revealed significant alternative profiling of mitochondrial and lysosomal proteins in ARPKD patients and an abrupt increase of lysosomal SGSH in both urinary exosomes and renal biopsy. Collectively, these findings may provide us new insight on the pathophysiology of the polycystic kidney due to PKHD1 deficiency, and the PKHD1 mosaicism needs to be taken close attention in genetic testing of ARPKD.