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.
Highlights
Nephronophthisis (NPH), an autosomal recessive disorder initially described in 1945 by Smith and Graham and in 1951 by Fanconi, is a chronic tubulointerstitial nephritis that uniformly progresses to end-stage renal disease (ESRD) [1, 2]
As with other genes implicated in cystic kidney diseases, most mutated proteins responsible for Meckel-Gruber syndrome (MKS) and JS have been shown to be localized to kidney primary cilia, further suggesting a connection between these syndromes
Tory et al found that some patients with NPH and at least one JS-related neurological symptom had both an NPHP1 deletion and either a heterozygous NPHP6 or AHI1 mutation [35]. These findings demonstrate that similar to the inheritance patterns described in Bardet-Biedl syndrome (BBS), NPH, at least in some patients, follows a digenic or oligogenic inheritance with heterozygous mutations in different genes in the same patients
Summary
Nephronophthisis (NPH), an autosomal recessive disorder initially described in 1945 by Smith and Graham and in 1951 by Fanconi, is a chronic tubulointerstitial nephritis that uniformly progresses to end-stage renal disease (ESRD) [1, 2]. Georges et al reported on four patients, from three different families, with RP responsible for severe visual impairment during childhood who developed chronic interstitial nephritis with histological lesions characteristic of NPH and renal failure only between 42 and 56 years of age [21]. As with other genes implicated in cystic kidney diseases, most mutated proteins responsible for MKS and JS have been shown to be localized to kidney primary cilia, further suggesting a connection between these syndromes.
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