Nephronophthisis

2000

Pediatric Nephrology, 2011

Nephronophthisis (NPHP) is an autosomal recessive kidney disease characterized by tubular basement membrane disruption, interstitial infiltration, and tubular cysts. NPHP leads to end-stage renal failure (ESRD) in the first three decades of life and is the most frequent genetic cause of chronic renal failure in children and young adults. Extrarenal manifestations are known, such as retinitis pigmentosa, brainstem and cerebellar anomalies, liver fibrosis, and ocular motor apraxia type Cogan. We report on a Turkish family with clinical signs of nephronophthisis. The phenotype occurred in two generations and therefore seemed to be inherited in an autosomal dominant pattern. Nevertheless, a deletion analysis of the NPHP1 gene on chromosome 2 was performed and showed a homozygous deletion. Analysis of the family pedigree indicated no obvious consanguinity in the last three generations. However, haplotype analysis demonstrated homozygosity on chromosome 2 indicating a common ancestor to the parents of all affected individuals. NPHP1 deletion analysis should always be considered in patients with apparently dominant nephronophthisis. Furthermore, three out of four patients developed ESRD between 27 and 43 years of age, which may be influenced by yet unknown modifier genes.

Pediatric Nephrology, 2010

Sirs, Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most frequent genetic cause for end-stage renal disease (ESRD) in the first three decades of life. Homozygous deletions in the NPHP1 gene account for approximately 21% of all ...

American Journal of Kidney Diseases, 2004

Nephronophthisis (NPH) is an autosomal recessive kidney disease characterized by tubular basement membrane disruption, interstitial infiltration, and tubular cysts. NPH leads to end-stage renal failure in the first 2 decades of life. Four genes responsible for different types of NPH have been identified: NPHP1, NPHP2, NPHP3, and NPHP4. The NPHP1 gene encodes nephrocystin; NPHP2, inversin; NPHP3, nephrocystin-3; and NPHP4, nephrocystin-4. We report 3 siblings from a consanguineous family with NPH who were previously described as carrying a homozygous mutation in the NPHP4 gene. Renal imaging showed cysts in the children. The histological picture of NPHP4 showed the same characteristic features as those known for NPHP1 and NPHP3. Progression to end-stage renal disease occurred between the ages of 17 and 22 years. None of the renal transplants showed recurrence of the disease. Retinitis pigmentosa was absent in all affected family members.

Irish Journal of Medical Science (1971 -), 2015

Aims Nephronophthisis (NPHP) is an autosomal recessive cystic disease of the kidney with main characteristic features of polyuria/polydipsia, mild or absent proteinuria, interstitial fibrosis, and tubular cysts. NPHP is responsible for 5-10 % of inheritable end-stage renal disease (ESRD) cases. We investigated the clinical features and genetic cause of NPHP in a Persian family with three siblings affected by tubulointerstitial nephropathy reaching ESRD in adulthood. Methods Uromodulin (UMOD), known to be involved in adult medullary cystic kidney disease, and nephronophthisis 1 (NPHP1) were investigated in the genomic DNA of the probands using DNA sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis and molecular karyotyping. Results No mutation was detected in UMOD. Copy number variation analysis of the NPHP1 gene using the commercially available MLPA kit identified a recurrent large homozygous deletion encompassing all NPHP1 exons. The parents were heterozygous for this deletion. Whole genome array-CGH analysis confirmed a homozygous deletion on chromosome 2q13, NPHP1 site, and revealed that the size of the copy number loss was approximately 102 Kbp. Conclusion This is the first report of determination of an NPHP1 deletion size using routine diagnostic methods. The results of this study expand the knowledge about the genotype-phenotype correlations in NPHP1, and have implications for genetic counseling and family planning advice for other affected families. This is the first molecular analysis of NPHP1 in an Iranian kindred.

Journal of the American Society of Nephrology, 2007

Joubert syndrome (JS) is an autosomal recessive disorder that is described in patients with cerebellar ataxia, mental retardation, hypotonia, and neonatal respiratory dysregulation. Kidney involvement (nephronophthisis or cystic renal dysplasia) is associated with JS in one fourth of known cases. Mutations in three genes-AHI1, NPHP1, and NPHP6-have been identified in patients with JS. However, because NPHP1 mutations usually cause isolated nephronophthisis, the factors that predispose to the development of neurologic involvement are poorly understood. In an attempt to identify such genetic determinants, a cohort of 28 families with nephronophthisis and at least one JS-related neurologic symptom were screened for mutations in AHI1, NPHP1, and NPHP6 genes. NPHP1 and NPHP6 homozygous or compound heterozygous mutations were found in 13 (46%) and six (21%) unrelated patients, respectively. Two of the 13 patients with NPHP1 mutations carried either a heterozygous truncating mutation in NPHP6 or a heterozygous missense mutation in AHI1. Furthermore, five patients with NPHP1 mutations carried the AHI1 variant R830W, which was predicted to be "possibly damaging" and was found with significantly higher frequency than in healthy control subjects and in patients with NPHP1 mutations without neurologic symptoms (five of 26 versus four of 276 and three of 152 alleles; P < 0.001 and P < 0.002, respectively). In contrast to the variable neurologic and milder retinal phenotype of patients with NPHP1 mutations, patients with NPHP6 mutations presented with a more severe neurologic and retinal phenotype. In conclusion, NPHP1 and NPHP6 are major genes of nephronophthisis associated with JS. Epistatic effects that are provided by heterozygous NPHP6 and AHI1 mutations and variants may contribute to the appearance of extrarenal symptoms in patients with NPHP1 mutations.

2012

Nephronophthisis (NPHP) is a recessive disorder of the kidney that is the leading genetic cause of end-stage renal failure in children. Egypt is a country with a high rate of consanguineous marriages; yet, only a few studies have investigated the clinical and molecular characteristics of NPHP and related ciliopathies in the Egyptian population. We studied 20 children, from 17 independent families, fulfilling the clinical and the ultrasonographic criteria of NPHP. Analysis for a homozygous deletion of the NPHP1 gene was performed by polymerase chain reaction on the genomic DNA of all patients. Patients were best categorized as 75% juvenile NPHP, 5% infantile NPHP, and 20% Joubert syndrome-related disorders (JSRD). The mean age at diagnosis was 87.5 + 45.4 months, which was significantly late as compared with the age at onset of symptoms, 43.8 ± 29.7 months (P <0.01). Homozygous NPHP1 deletions were detected in six patients from five of 17 (29.4%) studied families. Our study demonstrates the clinical phenotype of NPHP and related disorders in Egyptian children. Also, we report that homozygous NPHP1 deletions account for 29.4% of NPHP in the studied families in this cohort, thereby confirming the diagnosis of type-1 NPHP. Moreover, our findings confirm that NPHP1 deletions can indeed be responsible for JSRD.

The Journal of Pediatrics, 1981

2010

Human mutation, 2005

Nephronophthisis (NPH), a recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal disease in the first two decades of life. Mutations in three genes (NPHP1, 2, and 3) were identified as causative. Extrarenal manifestations are known, such as retinitis pigmentosa (Senior-Loken syndrome, SLS) and ocular motor apraxia type Cogan. Recently, we identified a novel gene (NPHP4) as mutated in NPH. To date, a total of only 13 different NPHP4 mutations have been described. To determine the frequency of NPHP4 mutations, we performed mutational analysis by direct sequencing of all 30 NPHP4 exons in 250 different patients with isolated NPH, SLS, or Cogan syndrome ascertained worldwide over 14 years. We identified 23 novel NPHP4 sequence variants in 26/250 different patients (10%). Interestingly, we detected homozygous or compound heterozygous mutations of NPHP4 in only 6/250 different patients (2.4%), but only one heterozygous NPHP4 sequence variant in 20/250 diff...