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Review
. 2011 Feb;26(2):181-94.
doi: 10.1007/s00467-010-1585-z. Epub 2010 Jul 22.

Nephronophthisis

Matthias T F Wolf  1 , Friedhelm Hildebrandt
Affiliations
Review

Nephronophthisis

Matthias T F Wolf et al. Pediatr Nephrol. 2011 Feb.

Abstract

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and the most frequent genetic cause of end-stage renal disease up to the third decade of life. It is caused by mutations in 11 different genes, denoted nephrocystins (NPHP1-11, NPHP1L). As an increasing number of these genes are identified, our knowledge of nephronophthisis is changing, thereby improving our understanding of the pathomechanisms in NPHP. Recent publications have described ciliary expression of nephrocystins together with other cystoproteins, such as polycystins 1 and 2 and fibrocystin. These findings have shifted our focus to a pathomechanism involving defects in ciliary function (ciliopathy) and planar cell polarity (PCP). In addition, discoveries of new nephrocystin genes have shown that the disease spectrum of NPHP is much broader than previously anticipated. Different forms of mutations within the same NPHP gene can cause different disease severity. In this review, we highlight the different hypotheses on the pathomechanisms for NPHP and underline the clinical variability of this disease. The clinical spectrum has become even more complex with the possibility of oligogenicity in NPHP.

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Figures

Fig 1
Fig 1. Renal ultrasound in NPHP
The renal ultrasound shows smaller bilateral kidneys, increased echogenicity (compare to abnormally lower echogenicity of liver), decreased cortico-medullary differentiation, and cortico-medullary cyst formation.
Fig 2
Fig 2. Renal histopathology in NPHP
Renal histopathology in NPHP is characterized by the triad of tubular cysts, tubular basement membrane disruption, and interstitial fibrosis with interstitial cell infiltration. PAS staining, magnification 20x.
Fig 3
Fig 3. The “molar tooth sign” is a classical neuroradiological characteristic of JS
The “molar tooth sign” (shown in box) on a brain magnetic resonance imaging (MRI). Brain MRI axial image at the level of the superior cerebellar peduncles of a JS patient. The “molar tooth sign” is characterized by cerebellar vermis aplasia, thickened and elongated superior cerebellar peduncles, and a deepened interpeduncular fossa.
Fig 4
Fig 4. Subcellular localization of the nephrocystins
Nephrocystins are detected in the primary cilia, basal bodies, the mitotic spindle, focal adhesions and adherens junctions. Most nephrocystins are expressed in the primary cilium (see enlarged box), the basal body (BB) and centrosomes (Cen) in a cell cycle-dependent manner. NPHP1 is expressed in the transition zone (TZ), focal adhesion plaques (FAP), adherens junctions (AJ), and tight junctions (TJ). Arrows in the cilium show the directions of the anterograde and retrograde transport along the microtubule transport. The intraflagellar transport is mediated by kinesin 2, a heterotrimeric protein that is composed of two motor units (Kif3a and Kif3b) and one nonmotor unit (KAP3). Sensory cilia transfer external stimuli. Wnt and hedgehog (Shh) signaling interfere with planar cell polarity by orientation of centrosomes and mitotic spindles. Adapted from Watnick and Germino.
Fig 5
Fig 5. Altered planar cell polarity causes cyst formation
Correct orientation of the mitotic spindle and centrosomes of renal tubular epithelial cells are especially during development required for proper growth of the longitudinal axis of the tubule (A). If the apical-basolateral polarity is disrupted a dilated tubule or cyst would develop (B). Non-canonical Wnt signaling is involved in proper cell orientation. Urinary flow in the renal tubules could provide signaling via cilia about cellular orientation. Adapted from Germino 2005.
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