Nephronophthisis

Abstract

Nephronophthisis (NPH) is an autosomal recessive disease characterized by a chronic tubulointerstitial nephritis that progress to terminal renal failure during the second decade (juvenile form) or before the age of 5 years (infantile form). In the juvenile form, a urine concentration defect starts during the first decade, and a progressive deterioration of renal function is observed in the following years. Kidney size may be normal, but loss of corticomedullary differentiation is often observed, and cysts occur usually after patients have progressed to end-stage renal failure. Histologic lesions are characterized by tubular basement membrane anomalies, tubular atrophy, and interstitial fibrosis. The infantile form is characterized by cortical microcysts and progression to end-stage renal failure before 5 years of age. Some children present with extrarenal symptoms: retinitis pigmentosa (Senior-Løken syndrome), mental retardation, cerebellar ataxia, bone anomalies, or liver fibrosis. Positional cloning and candidate gene approaches led to the identification of eight causative genes (NPHP1, 3, 4, 5, 6, 7, 8, and 9) responsible for the juvenile NPH and one gene NPHP2 for the infantile form. NPH and associated disorders are considered as ciliopathies, as all NPHP gene products are expressed in the primary cilia, similarly to the polycystic kidney disease (PKD) proteins.

Fig. 1

Renal histology of nephronophthisis. Cross-section of kidney showing diffuse interstitial fibrosis and various tubular changes. Some tubules are collapsed, others are surrounded by thickened tubular basement membranes. Note the laminated and wrinkled appearance of some tubular basement membrane segments as well as the abrupt attenuation of others in the same tubule (Light microscopy; magnification ×360; from Marie-Claire Gubler)

Fig. 2

Retinitis pigmentosa. Ophtalmoscopic examinations of a control subject (a) and an affected individual (b) showing typical retinitis pigmentosa fundus characterized by very thin retinal vessels, retinal pigment epithelium atrophy, abnormal pigmentary migrations, and pallor of the optic disk

Fig. 3

Molar tooth sign on brain magnetic resonance imaging (MRI). Brain MRI axial image at the level of the superior cerebellar peduncles of a control subject (a) and an affected individual (b) showing abnormally increased depth of the interpeduncular fossa, narrowing of the midbrain tegmentum, and thickening of the superior cerebellar peduncles, all of which contribute to the radiologic feature known as the molar tooth sign (white arrow)

Fig. 4

Genes implicated in nephronophthisis, retinitis, and Joubert syndrome. Different associations between these syndromes and the corresponding mutated genes. The most frequently mutated genes are indicated in large characters. NPHP7 and NPHP9 genes are not represented because of their low mutation rate. Extrarenal disorders associated with mutation in the NPHP2 gene are not indicated. Two patients with NPHP8 mutations and mild retinitis have been reported [34, 74]

Fig. 5

Schematic representation of the tubular epithelium and subcellular localization of the nephrocystin proteins. Nephrocystins localize to different subcellular compartments within the cell in a cell-cycle-dependent manner. Most nephrocystins interact with one another, forming a nephrocystin complex. In polarized renal tubular cells, all nephrocystin proteins localized to the primary cilia at the base of the cilium (basal body) and in a punctate pattern along the ciliary axoneme, suggesting their transport along the microtubule system (red arrows). Nephrocystin-1, nephrocystin-4, and inversin also localize to the cell–cell junctions and interact with focal adhesion proteins (p130Cas, Pyk2). Nephrocystins also associate with proteins associated directly with the microtubular and actin cytoskeleton (tubulins, tensin, and filamin). These localizations suggest a role for nephrocystins in modulating the cytoskeleton and maintaining epithelial-cell polarity. During cell cycle, nephrocystins localize to the centrosome. Moreover, during cell division, inversin, nephrocystin-4 and nephrocystin-6 localize to the mitotic spindle. In addition, inversin and nephrocystin-6 bind the anaphase-promoting complex (APC2) and activating transcription factor (ATF4), respectively, suggesting their potential involvement in cell-cycle regulation. The transcription factor nephrocystin-7/GLIS2 localized to both nucleus and primary cilia, as did the other NPHP proteins in renal epithelial cells

Fig. 6

Decision algorithm for genetic analyses when nephronophthisis is suspected on clinical and radiological basis. At first, NPHP1 or NPHP2 genes should be screened for mutations, depending on the age at onset of end-stage renal disease. The other genes are analyzed in function of extrarenal symptoms. NPHP3, NPHP4, NPHP7, and NPHP9 genes are currently not sequenced for diagnostic purposes because of their low mutation rate. RP retinitis pigmentosa