Renal Ciliopathies

Abstract

Defects in centrosome and cilium function lead to phenotypically related syndromes called ciliopathies. Cilia are microtubule‐based antennae that detect and orchestrate extracellular stimuli. As environmental rheostats and cellular signalling centres, they mediate multiple pathways that if disrupted lead to early developmental defects and cancer. Cystic kidney disorders such as polycystic kidney disease (ADPKD/ARPKD) and nephronophthisis (NPHP) play a central role in the elucidation of ciliopathies, and practically, all cilia‐related disorders can show renal cysts. In addition, patients may present with extrarenal manifestations in other organs. An accurate genetic diagnosis is crucial for genetic counselling, prenatal diagnostics and the clinical management of patients and their families. The increasing number of genes that have to be considered in patients with ciliopathies is challenging to address by conventional techniques and largely benefits from next‐generation sequencing (NGS)‐based approaches.

Key Concepts

  • Polycystic kidney disease (PKD) constitutes the most common life‐threatening genetic disorder and affects about 10–15 million people worldwide.
  • The majority of patients with PKD harbour mutations in the typical genes for ARPKD and ADPKD; however, mutations in other genes can mimic PKD.
  • PKD paved the way for other cilia‐related disorders of which most can show renal cysts.
  • Renal ciliopathies are characterized by tremendous clinical and genetic heterogeneity.
  • Patients may present with extrarenal manifestations in other organs (e.g. liver cysts, heart defects, retinal degeneration, deafness and intracranial aneurysms).
  • The underlying genotype can usually be identified by next‐generation sequencing (NGS)‐based approaches that allow the parallel analysis of all disease genes.
  • An accurate genetic diagnosis is crucial for genetic counselling, prenatal diagnostics and clinical management (with early detection and treatment of complications).

Keywords: cilia/ciliopathies; cystic kidneys; polycystic kidney disease (ADPKD/ARPKD); nephronophthisis (NPHP); Meckel syndrome (MKS); Joubert syndrome (JBTS); Bardet–Biedl syndrome (BBS); Alstrom syndrome; short‐rib polydactyly syndromes; Jeune syndrome (ATD)

Figure 1. Schematic diagram of a primary cilium and associated processes. Polycystic kidney disease is controlled by a defined network of different genes/proteins discussed in this article. Cilia are small antennae that detect a variety of different extracellular stimuli and orchestrate multiple signalling pathways with nuclear trafficking of some molecules (e.g. C‐termini of polycystin‐1 (PC1) and fibrocystin/polyductin (FPC)). The inner ciliary structure is defined by the axoneme composed of nine microtubule doublets derived from the basal body and mother centriole of the centrosome. Along this microtubule core, the (anterograde) transport of proteins towards the tip of the cilium and in the retrograde direction towards the cell body is organized by an elaborate process called intraflagellar transport (IFT).
Figure 2. Organs frequently affected in cilia‐related disorders.
Figure 3. (a–g) Broad clinical spectrum of ciliopathies ranging from single‐organ involvement to complex, early embryonic disorders in which multiple organs can be affected.
Figure 4. (a, c) Macroscopic appearance of advanced‐stage ADPKD showing enlarged kidneys with multiple cysts that almost completely destructed and replaced the renal parenchyma. (b) On cut section, multiple cysts in the cortex and medulla can be seen that vary considerably in size and appearance, from a few millimetres to diameters of many centimetres. Reproduced with permission from Bergmann, Pediatr Nephrol 2014 © Springer.
Figure 5. Autosomal recessive polycystic kidney disease (ARPKD). (a) Baby with distended abdomen due to voluminous kidneys that lead to respiratory problems. (b) Abdominal situs of a perinatally demised ARPKD patient with symmetrically enlarged kidneys that maintain their reniform configuration. (c) Potter's phenotype with distinctive facial features due to lack of amniotic fluid. (d–h) Renal ultrasound of babies and young children with ARPKD. Symmetrically enlarged echogenic kidneys with fusiform dilations of collecting ducts and distal tubules arranged radially throughout the renal parenchyma from medulla to cortex. Reproduced with permission from Bergmann, Pediatr Nephrol 2014 © Springer.
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Bergmann, Carsten(Jan 2015) Renal Ciliopathies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025223]