Mutations in NPHP3 can produce diverse phenotypes. Mutations were originally identified in a large Venezuelan kindred who exhibited nephronophthisis (NPHP). Mutations in NPHP3 were associated with hepatic fibrosis and retinal degeneration in some affected individuals. Recently the phenotype of NPHP3 mutations has been expanded to include Meckel-Gruber like syndrome (PMID:19066617).
Nephronophthisis, an autosomal recessive cystic kidney disease, is the most frequent monogenic cause of renal failure in childhood. Omran et al. (2000) described a form of this disorder, adolescent nephronophthisis, that they considered clearly distinct by clinical and ... Nephronophthisis, an autosomal recessive cystic kidney disease, is the most frequent monogenic cause of renal failure in childhood. Omran et al. (2000) described a form of this disorder, adolescent nephronophthisis, that they considered clearly distinct by clinical and genetic findings. They evaluated clinical symptoms and renal pathology in a large, 340-member consanguineous Venezuelan kindred. Most of the patients suffered from anemia when they first came to medical attention. Onset of terminal renal failure was compared with that in a historical sample of juvenile nephronophthisis. In adolescent nephronophthisis, onset of terminal renal failure occurred significantly later (median age, 19 years; quartile borders, 16.0 and 25.0 years) than in juvenile nephronophthisis (median age, 13.1 years; quartile borders, 11.3 and 17.3 years; Wilcoxon test P = 0.0069). Omran et al. (2000) concluded that histologic findings in adolescent nephronophthisis are generally not distinguishable from those of juvenile nephronophthisis. Renal pathology in adolescent NPHP is characterized by alterations of tubular basement membranes, tubular atrophy and dilatation, sclerosing tubulointerstitial nephropathy, and renal cyst development predominantly at the corticomedullary junction (Olbrich et al., 2003). Simpson et al. (2009) reported 12 infants from 6 Old Order Amish families with lethal neonatal nephronophthisis-3. All 12 unaffected parents descended from a common ancestral couple who lived in the community during the 19th century. Most of the pregnancies were associated with oligohydramnios. Clinical features included cystic kidneys, low-set ears, and small lungs with respiratory insufficiency. One infant was reported to have situs inversus, and 2 had absent bladder. Simpson et al. (2009) noted that few affected infants had complete medical evaluations due to the severe nature of the disease, and no autopsy information was available. Thus, additional extrarenal manifestations may have been present. Tory et al. (2009) reported 7 probands with genetically confirmed infantile-onset NPHP3. The median age at onset was 30 months (range 2 to 48), and the median age at end-stage renal disease was 36 months (range 6 to 52). All but 1 of the patients were hypertensive. Renal ultrasound revealed hyperechogenic kidneys in all patients, with variable kidney sizes, but only 2 had renal cysts. Six renal biopsies showed diffuse tubulointerstitial lesions, and some cortical tubules showed cystic dilatation. Two patients showed thickening and splitting of the basement membrane, characteristic of juvenile NPHP. Marked thickening of the arterial walls was observed in all cases. All patients showed extrarenal manifestations, with hepatic involvement and liver fibrosis affecting all but 1 patient. Other extrarenal manifestations included cone-shaped epiphyses in 2, heart valve or septal defects in 2, and retinitis pigmentosa in 1.
Olbrich et al. (2003) reported the identification of a novel gene, NPHP3, encoding a 1,330-amino acid protein that interacts with nephrocystin-1 (607100), the protein that is mutant in nephronophthisis-1 (NPHP1; 256100). They described mutations in the NPHP3 gene ... Olbrich et al. (2003) reported the identification of a novel gene, NPHP3, encoding a 1,330-amino acid protein that interacts with nephrocystin-1 (607100), the protein that is mutant in nephronophthisis-1 (NPHP1; 256100). They described mutations in the NPHP3 gene (608002.0001-608002.0003) in families with isolated nephronophthisis and in families with nephronophthisis with associated hepatic fibrosis or tapetoretinal degeneration. In 12 infants from 6 Old Order Amish families with lethal neonatal nephronophthisis-3, Simpson et al. (2009) identified a homozygous nonsense mutation in the NPHP3 gene (R702X; 608002.0009). Tory et al. (2009) identified 9 different NPHP3 mutations in 7 (16%) of 43 unrelated probands with infantile-onset NPHP and end-stage renal failure before age 5 years. Thirteen different mutations in the INVS gene (see, e.g., 243305.0003-235505.0005) were found in 16 (37%) families. Overall, those with a INVS mutations had a faster deterioration compared to those with NPHP3 mutations, and those with NPHP3 mutations tended to have liver abnormalities.