We used whole-exome sequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, <i>ALG9</i>, and <i>in vitro</i> cell-based assays of PC1 protein maturation to functionally validate it.
A grandmother with the PKD1 gene mutation in mosaicism (p.Val1105ArgfsX4) and with mild clinical course of ADPKD (end stage renal failure at the age of 77) seemed to have ADPKD because of PKD2 gene mutation.
Although both variants were predicted to be damaging to the mutant protein, only Y528C co-segregated with all of the PKD1-affected individuals in NFL10.
Mutations in PKD1 and PKD2, the genes encoding the proteins polycystin-1 (PC1) and polycystin-2 (PC2), cause autosomal dominant polycystic kidney disease (ADPKD).
The rest of the patient samples also showed few variants in ADPKD (Autosomal Dominant Polycystic Kidney Disease) disease causing genes PKD1 and PKD2 i.e.
Further assessment of the mutants revealed impaired autophagic flux, which was conserved in kidney epithelial cells derived from both Pkd1-null mice and ADPKD patients.
PKD1 and PKD2 variants were identified by direct gene sequencing and/or multiplex ligation-dependent probe amplification (MLPA) in 125 unrelated patients of ADPKD.
Technical Evaluation: Identification of Pathogenic Mutations in PKD1 and PKD2 in Patients with Autosomal Dominant Polycystic Kidney Disease by Next-Generation Sequencing and Use of a Comprehensive New Classification System.
Unopposed cAMP stimulated hyperphosphorylation of PC2 in the absence of functional PC1 could contribute to cyst initiation in PKD1 patients and represents a new molecular paradigm in understanding ADPKD pathogenesis.
Polycystin-1 (PC1) is a large transmembrane protein important in renal differentiation and defective in most cases of autosomal dominant polycystic kidney disease (ADPKD), a common cause of renal failure in adults.
To determine whether the presence of CF with the expression of mutated CFTR proteins modifies cyst formation in ADPKD, we studied a large family with both inherited diseases.ADPKD in this family is linked to PKD1.
Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, and duplication sequences of PKD1.