Refining genotype–phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants

Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations

“…In autosomal recessive polycystic kidney disease (ARPKD [MIM: 263200 ]) for instance, one quarter of affected individuals need renal replacement therapy by the age of 15 years and more than half show signs of portal hypertension by then. 12 Similarly, end-stage kidney disease due to nephronophthisis usually develops before adulthood. 9 These early presentations, often with considerable disease burden already manifest prenatally during embryonic development, limit our ability to investigate the initial triggers of organ fibrosis, to study the natural course of disease, and to provide therapeutic windows for potential interventional studies.…”

Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases

“…ADPKD is mainly associated with mutations in the PKD1 or PKD2 genes encoding the polycystin-1 and -2 proteins (PC1 and PC2), respectively (Dong et al, 2019). The primary cause of ARPKD is mutations in the PKHD1 gene encoding the fibrocystin/polyductin protein (FPC; Burgmaier et al, 2021).…”

Is There a Functional Role of Mitochondrial Dysfunction in the Pathogenesis of ARPKD?

“…For ARPKD it was shown by various groups that biallelic truncating variants are associated with severe phenotypes. A recent study extended the findings and revealed that for missense variants the affected region in PKHD1 also seems to be important (10). In a study on 304 children with the clinical diagnosis of ARPKD and detected PKHD1 variants it was found that patients with either two missense variants affecting the amino acids 709-1837 or a null variant and a missense variant in this region less frequently showed progression to chronic kidney failure when being compared during their follow-up when compared to patients with variants affecting other regions of PKHD1.…”

“…In a study on 304 children with the clinical diagnosis of ARPKD and detected PKHD1 variants it was found that patients with either two missense variants affecting the amino acids 709-1837 or a null variant and a missense variant in this region less frequently showed progression to chronic kidney failure when being compared during their follow-up when compared to patients with variants affecting other regions of PKHD1. On the other hand patients with variants affecting the amino acids 2625-4074 showed less favorable hepatic outcome (10). The underlying molecular mechanisms of these associations remain to be explored.…”