Insights into Autosomal Dominant Polycystic Kidney Disease from Genetic Studies

Abstract

Autosomal dominant polycystic kidney disease is the most common monogenic cause of ESKD. Genetic studies from patients and animal models have informed disease pathobiology and strongly support a "threshold model" in which cyst formation is triggered by reduced functional polycystin dosage below a critical threshold within individual tubular epithelial cells due to (1) germline and somatic PKD1 and/or PKD2 mutations, (2) mutations of genes (e.g., SEC63, SEC61B, GANAB, PRKCSH, DNAJB11, ALG8, and ALG9) in the endoplasmic reticulum protein biosynthetic pathway, or (3) somatic mosaicism. Genetic testing has the potential to provide diagnostic and prognostic information in cystic kidney disease. However, mutation screening of PKD1 is challenging due to its large size and complexity, making it both costly and labor intensive. Moreover, conventional Sanger sequencing-based genetic testing is currently limited in elucidating the causes of atypical polycystic kidney disease, such as within-family disease discordance, atypical kidney imaging patterns, and discordant disease severity between total kidney volume and rate of eGFR decline. In addition, environmental factors, genetic modifiers, and somatic mosaicism also contribute to disease variability, further limiting prognostication by mutation class in individual patients. Recent innovations in next-generation sequencing are poised to transform and extend molecular diagnostics at reasonable costs. By comprehensive screening of multiple cystic disease and modifier genes, targeted gene panel, whole-exome, or whole-genome sequencing is expected to improve both diagnostic and prognostic accuracy to advance personalized medicine in autosomal dominant polycystic kidney disease.

Keywords: Kidney Genomics Series; polycystic kidney disease.

Figure 1.

Schematic representation of endoplasmic reticulum maturation and N-glycosylation of nascent polycystin-1 (PC-1) and polycystin-2 (PC-2). Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD); mutations in SEC61B, SEC63, ALG8, GANAB, and PRKCSH cause autosomal dominant polycystic liver disease; mutations in PKHD1 cause autosomal recessive polycystic kidney disease; and mutations in ALG9 and GANAB cause atypical ADPKD. All conditions have phenotypic overlap and include some degree of kidney and liver cysts, and they are related to alterations in the functional dosage of mature PC-1/PC-2 complex.

Figure 2.

Insights into pathobiology of ADPKD from human and animal genetic studies. AMPK, 5ʹ-AMP–activated protein kinase; ER, endoplasmic reticulum; ERK, extracellular signal–regulated kinase; JAK-STAT, Janus kinase-signal transducer and activator of transcription signaling pathway; mTOR, mammalian target of rapamycin.

Figure 3.

Clinical scenarios of atypical ADPKD presentations and potential genetic explanations.

Figure 4.

Effects of digenic disease on functional polycystin dosage and cystic disease severity. hp, hypomorphic variant.