Nephronophthisis and related syndromes

Abstract

Purpose of review: Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most common genetic disorders causing end-stage renal disease (ESRD) in children and adolescents. NPHP is a genetically heterogenous disorder with 20 identified genes. NPHP occurs as an isolated kidney disease, but approximately 15% of NPHP patients have additional extrarenal symptoms affecting other organs [e.g. eyes, liver, bones and central nervous system (CNS)]. The pleiotropy in NPHP is explained by the finding that almost all NPHP gene products share expression in primary cilia, a sensory organelle present in most mammalian cells. If extrarenal symptoms are present in addition to NPHP, these disorders are classified as NPHP-related ciliopathies (NPHP-RC). This review provides an update about recent advances in the field of NPHP-RC.

Recent findings: The identification of novel disease-causing genes has improved our understanding of the pathomechanisms contributing to NPHP-RC. Multiple interactions between different NPHP-RC gene products have been published and outline the interconnectivity of the affected proteins and shared pathways.

Summary: The significance of recently identified genes for NPHP-RC is discussed and the complex role and interaction of NPHP proteins in ciliary function and cellular signalling pathways is highlighted.

Fig. 1. Imaging findings by renal ultrasound in NPHP

With advancing kidney disease small kidneys are detected bilaterally. There is development of hyperechogenic kidneys (compare to lower echogenicity of the liver) with cysts along the cortico-medullary border.

Fig. 2. Renal histopathology in NPHP

Characteristically, histopathology in NPHP is characterized by tubular cysts, tubular atrophy, interstitial and periglomerular fibrosis, tubulo-interstitial infiltration, and tubular basement membrane disruption. Periodic acid-Schiff (PAS) staining, magnification 20x.

Fig. 3. Magnetic resonance imaging (MRI) of the brain in Joubert syndrome

The “molar tooth sign” develops due to cerebellar vermis hypoplasia and can easily be detected by MRI (boxed). The “molar tooth sign” has become the classical neuroradiological indicator for Joubert syndrome.

Fig. 4. Model of ciliary transport and architecture

Primary cilia protrude from the apical plasma membrane of the cell into the tubular lumen. At the base of the primary cilium is the basal body located from which the cilium is initially assembled. The inside of the cilium contains the ciliary axoneme. Assembly and function of primary cilia depend on ciliary transport, also called intraflagellar transport (IFT). Transport occurs in both directions of the axoneme along microtubules. IFT from the ciliary base to the ciliary tip is called anterograde transport and is driven by the kinesin-2 motor and IFT-B complex. IFT from the ciliary tip back to the base is called retrograde IFT and is controlled by dynein-2 motor and IFT-A complex. The IFT-A complex consists of six different proteins whereas the IFT-B complex contains at least 14 different proteins. Mutations in all members of the IFT-A complex result in skeletal dysplasia with NPHP (reprinted with permission from 48).

Fig. 5. The photoreceptor contains the connecting cilium

The photoreceptor consist of the rod outer (ROS) and rod inner segments (RIS), connected by the connecting cilium. Rhodopsin and other phototransducing substances are synthesized in the RIS as the ROS lacks any biosynthetic activity. Rhodopsin is sequestered in the light-sensing membranes of the ROS. Several Nephrocystins are localized in the ROS and the connecting cilium. BB, basal body; m, mitochrondria; N, nucleus; RTC, rhodopsin transport carrier; TGN, trans-golgi network (reprinted with permission from 43).

Fig. 6. Nephrocystins form different protein modules are expressed at different sites along the ciliary axoneme

In contrast to other proteins involved in cystic kidney disease (e.g. the BBSome) Nephrocystins form multiple smaller protein modules. The module Nephrocystin-1-4-8 is mostly expressed in the transition zone and is involved in apical organization of epithelial cells. The Nephrocystin-5-6 complex is localized in the basal body and is crucial for proper ciliogenesis. The MKS1-6 module links ciliary function to Sonic Hedgehog (Hh) signaling. Dysfunctional ciliogenesis disturbs Hh signaling which results in embryonic neural tube dorsalization and polydactyly. The bridging component consists of Nephrocystin-2-3-9 and is expressed along the entire axoneme. One may speculate if some of these protein modules correlate with extrarenal phenotypes: Nephrocystins-5 and -6 cause retinitis pigmentosa, altered MKS1 and 6 result in Meckel-Gruber and Joubert syndromes, and the components of the bridging component result in infantile NPHP and congenital heart defects (reprinted with permission from 71).