Disease relevance of NPHP1

• Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children [1].
• Nephronophthisis (NPHP), a group of autosomal recessive cystic kidney disorders, is the most common genetic cause of progressive renal failure in children and young adults [2].
• We describe mutations in NPHP3 in families with isolated NPHP and in families with NPHP with associated hepatic fibrosis or tapeto-retinal degeneration [2].
• The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD) [1].
• The only difference is a younger age at ESRD in NPH1 (median age of 13 years) when compared with NPH3 [3].

Psychiatry related information on NPHP1

• Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis [4].
• NPH3 shares with juvenile nephronophthisis (NPH1) the same disease manifestations such as polyuria, polydipsia, and secondary enuresis [3].

High impact information on NPHP1

• Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children [5].
• The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped [1].
• NPHP1, the only gene identified so far, encodes nephrocystin, which contains a Src homology 3 (SH3) domain and interacts with intracytoplasmic proteins involved in cell adhesion [6].
• In patients with a hemizygous deletion of the NPH1 region, additional point mutations were found in NPHP1 but not in MALL [7].
• Familial juvenile nephronophthisis (NPH) is a chronic autosomal recessive kidney disease responsible for 15% of end stage renal failure in children [8].

Chemical compound and disease context of NPHP1

• Nephronophthisis (previously described as familial juvenile nephronophthisis and medullary cystic disease) is characterized by insidious renal failure, its main features being increased urinary sodium loss, pitressin-resistant hypotomic polyuria, polydipsia, normal urine sediment and absence of hypertension [9].
• The Senior-Loken syndrome, also called Hereditary Renal Retinal Dystrophy is a rare disorder that combines a juvenile nephronophthisis-like disease with tapetoretinal degeneration [10].

Biological context of NPHP1

• We carried out haplotype analysis of families affected with nephronophthisis that were not linked to the NPHP1, NPHP2 or NPHP3 loci, using markers covering this region [6].
• The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome [11].
• The deletion occurred on both chromosomes 2q13 in one patient and heterozygously in combination with a point mutation of the NPHP1 gene in the other [4].
• CONCLUSION: Four NPH-families were neither linked to NPHP1 nor to NPHP3, indicating further genetic heterogeneity within the group of nephronophthisis [3].
• In 1 patient, we identified a novel deletion mutation including about half of exons of the NPHP1 gene [12].

Anatomical context of NPHP1

• This hypothesis is based on the fact that most src-homology 3-containing proteins are part of focal adhesion signaling complexes, on animal models that exhibit an NPH-like phenotype, and on the recent finding that nephrocystin binds to the protein p130(cas), a major mediator of focal adhesion signaling [13].
• A lack of functional nephrocystin may compromise Pyk2 signaling in a subset of renal epithelial cells [14].
• In this study, we demonstrated that nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies, and associates with microtubule component alpha-tubulin, suggesting a common role for the nephrocystin proteins in ciliary function [15].
• Nephrocystin was recently shown to interact and to co-localize with the microtubule component beta-tubulin to the primary cilia in renal epithelial cells, an organelle known to play a key role in the pathogenesis of cystic kidney diseases [15].
• Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes [15].

Associations of NPHP1 with chemical compounds

• The PHOT1 (NPH1) gene from Avena sativa specifies the blue light receptor for phototropism, phototropin, which comprises two FMN-binding LOV domains and a serine/threonine protein kinase domain [16].
• We present a statistical description of serial serum creatinine measurements in NPH1 [17].
• Severe tubular resistance to aldosterone in a child with familial juvenile nephronophthisis [18].

Other interactions of NPHP1

• Here we report the identification of NPHP3, encoding a novel 1,330-amino acid protein that interacts with nephrocystin [2].
• We here report identification of the gene (NPHP4) causing NPHP type 4, by use of high-resolution haplotype analysis and by demonstration of nine likely loss-of-function mutations in six affected families [19].
• Five nephrocystin (nephrocystin-1 to nephrocystin-5) genes, whose function is disrupted in NPH patients, have been identified and data indicate they form a complex at cell junctions and focal adhesions [20].
• At all four loci, linkage has also been demonstrated in families with the association of NPHP and retinitis pigmentosa, known as "Senior-Løken syndrome" (SLS) [19].
• Identification of the gene for NPHP type 1 had revealed nephrocystin as a novel docking protein, providing new insights into mechanisms of cell-cell and cell-matrix signaling [19].

Analytical, diagnostic and therapeutic context of NPHP1

• In this study, by large-scale genomic sequencing and pulsed-field gel electrophoresis analysis, we characterized the complex organization of the NPHP1 locus and determined the mutational mechanism that results in the large deletion observed in most patients [21].
• To study tissue expression and analyze amino acid sequence conservation of nephrocystin, the full-length murine Nphp1 cDNA sequence was obtained and Northern and in situ hybridization analyses were performed for extensive expression studies [22].
• Diseases with isolated involvement of the medulla (juvenile nephronophthisis/medullary cystic disease) or cortex are described as part of the differential diagnosis, they are heterogeneous and genetically only partly understood [23].
• This contig mapping provides the basis for cloning of this interval and for isolation of the NPH1 gene [24].
• The indication for nephrectomy was severe post-transplant polyuria secondary to the patient's underlying disease: juvenile nephronophthisis [25].

References