The Experts below are selected from a list of 1677 Experts worldwide ranked by ideXlab platform
Friedhelm Hildebrandt - One of the best experts on this subject based on the ideXlab platform.
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Gene mutation analysis in Iranian children with nephronophthisis: a two-center study.
Iranian journal of kidney diseases, 2015Co-Authors: Alaleh Gheissari, Maryam Harandavar, Friedhelm Hildebrandt, Daniela A. Braun, Maryam Sedghi, Nastaran Parsi, Alireza Merrikhi, Yahya Madihi, Farzaneh AghamohammadiAbstract:Introduction. Nephronophthisis is of the most commonly inherited ciliopathies that leads to end-stage renal disease in children. The NPHP1 gene is the first identified gene responsible for nephronophthisis and related diseases. This study assessed mutations of the NPHP1 gene in 16 Iranian families with at least one member presenting features of nephronophthisis. Materials and Methods. Fifty-seven patients diagnosed with chronic kidney disease or end-stage renal disease were referred to Imam Hossein Children Hospital, in Isfahan, Iran. The gene analysis study was carried on 16 patients and their first-degree relatives (40 DNA samples) suspicious of having nephronophthisis. The NPHP1 deletion analysis was performed for exons 5, 7, and 20 of the NPHP1 gene. Results. The patients' median age was 15 years. The mean and median age of the first presentation was 10.06 ± 2.59 years and 10.5 years, respectively. A homozygous deletion was identified in the NPHP1 gene spanning at least from exon 5 to exon 20 in two families. High-throughput mutation analysis identified a homozygous truncating mutation (c.1504C>T, p.R502*) in the NPHP5 in 5 families. Conclusions. By combining NPHP1 deletion analysis with multiplex-polymerase-chain-reaction-based high-throughput mutation analysis we could identify the molecular disease-cause in 7 of 15 families from Iran. In 8 families, the molecular disease cause remained unknown.
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Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy
Human Genetics, 2013Co-Authors: Jan Halbritter, Friedhelm Hildebrandt, Daniela A. Braun, Moumita Chaki, Susan J. Allen, Jonathan D. Porath, Katrina A. Diaz, Stefan Kohl, Neveen A. Soliman, Edgar A OttoAbstract:Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal-recessive cystic kidney diseases. More than 13 genes are implicated in its pathogenesis to date, accounting for only 40 % of all cases. High-throughput mutation screenings of large patient cohorts represent a powerful tool for diagnostics and identification of novel NPHP genes. We here performed a new high-throughput mutation analysis method to study 13 established NPHP genes ( NPHP1 – NPHP13 ) in a worldwide cohort of 1,056 patients diagnosed with NPHP-RC. We first applied multiplexed PCR-based amplification using Fluidigm Access-Array™ technology followed by barcoding and next-generation resequencing on an Illumina platform. As a result, we established the molecular diagnosis in 127/1,056 independent individuals (12.0 %) and identified a single heterozygous truncating mutation in an additional 31 individuals (2.9 %). Altogether, we detected 159 different mutations in 11 out of 13 different NPHP genes, 99 of which were novel. Phenotypically most remarkable were two patients with truncating mutations in INVS/NPHP2 who did not present as infants and did not exhibit extrarenal manifestations. In addition, we present the first case of Caroli disease due to mutations in WDR19/NPHP13 and the second case ever with a recessive mutation in GLIS2/NPHP7 . This study represents the most comprehensive mutation analysis in NPHP-RC patients, identifying the largest number of novel mutations in a single study worldwide.
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clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies a single center experience
Saudi Journal of Kidney Diseases and Transplantation, 2012Co-Authors: Neveen A. Soliman, Edgar A Otto, Friedhelm Hildebrandt, Susan J. Allen, Marwa M Nabhan, Ahmed M Badr, Maha Sheba, Sawsan Fadda, Ghada Gawdat, Hassan ElkikyAbstract: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.
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Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience.
Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation Saudi Arabia, 2012Co-Authors: Neveen A. Soliman, Edgar A Otto, Friedhelm Hildebrandt, Susan J. Allen, Marwa M Nabhan, Ahmed M Badr, Maha Sheba, Sawsan Fadda, Ghada Gawdat, Hassan El-kikyAbstract: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
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Genotype–phenotype correlation in 440 patients with NPHP-related ciliopathies
Kidney international, 2011Co-Authors: Moumita Chaki, Julia Hoefele, Edgar A Otto, Gokul Ramaswami, Susan J. Allen, Sabine Janssen, Carsten Bergmann, John R. Heckenlively, Friedhelm HildebrandtAbstract:Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal failure in the first three decades of life. Mutations in 13 genes ( NPHP1 - NPHP11 , AHI1 , and CC2D2A ) cause NPHP with ubiquitous expression of the corresponding proteins consistent with the multiorgan involvement of NPHP-related diseases. The genotype–phenotype correlation in these ciliopathies can be explained by gene locus heterogeneity, allelism, and the impact of modifier genes. In some NPHP-related ciliopathies, the nature of the recessive mutations determines disease severity. In order to define the genotype–phenotype correlation more clearly, we evaluated a worldwide cohort of 440 patients from 365 families with NPHP-related ciliopathies, in whom both disease-causing alleles were identified. The phenotypes were ranked in the order of severity from degenerative to degenerative/dysplastic to dysplastic. A genotype of two null alleles caused a range of phenotypes, with an increasing order of severity of NPHP1 , NPHP3 , NPHP4 , NPHP5 , NPHP2 , NPHP10 , NPHP6 , to AHI1 . Only NPHP6 showed allelic influences on the phenotypes; the presence of two null mutations caused dysplastic phenotypes, whereas at least one missense allele rescued it to a milder degenerative phenotype. We also found nine novel mutations in the NPHP genes. Thus, our studies have important implications for genetic counseling and planning of renal replacement therapy.
Edgar A Otto - One of the best experts on this subject based on the ideXlab platform.
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Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy
Human Genetics, 2013Co-Authors: Jan Halbritter, Friedhelm Hildebrandt, Daniela A. Braun, Moumita Chaki, Susan J. Allen, Jonathan D. Porath, Katrina A. Diaz, Stefan Kohl, Neveen A. Soliman, Edgar A OttoAbstract:Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal-recessive cystic kidney diseases. More than 13 genes are implicated in its pathogenesis to date, accounting for only 40 % of all cases. High-throughput mutation screenings of large patient cohorts represent a powerful tool for diagnostics and identification of novel NPHP genes. We here performed a new high-throughput mutation analysis method to study 13 established NPHP genes ( NPHP1 – NPHP13 ) in a worldwide cohort of 1,056 patients diagnosed with NPHP-RC. We first applied multiplexed PCR-based amplification using Fluidigm Access-Array™ technology followed by barcoding and next-generation resequencing on an Illumina platform. As a result, we established the molecular diagnosis in 127/1,056 independent individuals (12.0 %) and identified a single heterozygous truncating mutation in an additional 31 individuals (2.9 %). Altogether, we detected 159 different mutations in 11 out of 13 different NPHP genes, 99 of which were novel. Phenotypically most remarkable were two patients with truncating mutations in INVS/NPHP2 who did not present as infants and did not exhibit extrarenal manifestations. In addition, we present the first case of Caroli disease due to mutations in WDR19/NPHP13 and the second case ever with a recessive mutation in GLIS2/NPHP7 . This study represents the most comprehensive mutation analysis in NPHP-RC patients, identifying the largest number of novel mutations in a single study worldwide.
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clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies a single center experience
Saudi Journal of Kidney Diseases and Transplantation, 2012Co-Authors: Neveen A. Soliman, Edgar A Otto, Friedhelm Hildebrandt, Susan J. Allen, Marwa M Nabhan, Ahmed M Badr, Maha Sheba, Sawsan Fadda, Ghada Gawdat, Hassan ElkikyAbstract: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.
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Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience.
Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation Saudi Arabia, 2012Co-Authors: Neveen A. Soliman, Edgar A Otto, Friedhelm Hildebrandt, Susan J. Allen, Marwa M Nabhan, Ahmed M Badr, Maha Sheba, Sawsan Fadda, Ghada Gawdat, Hassan El-kikyAbstract: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
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Genotype–phenotype correlation in 440 patients with NPHP-related ciliopathies
Kidney international, 2011Co-Authors: Moumita Chaki, Julia Hoefele, Edgar A Otto, Gokul Ramaswami, Susan J. Allen, Sabine Janssen, Carsten Bergmann, John R. Heckenlively, Friedhelm HildebrandtAbstract:Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal failure in the first three decades of life. Mutations in 13 genes ( NPHP1 - NPHP11 , AHI1 , and CC2D2A ) cause NPHP with ubiquitous expression of the corresponding proteins consistent with the multiorgan involvement of NPHP-related diseases. The genotype–phenotype correlation in these ciliopathies can be explained by gene locus heterogeneity, allelism, and the impact of modifier genes. In some NPHP-related ciliopathies, the nature of the recessive mutations determines disease severity. In order to define the genotype–phenotype correlation more clearly, we evaluated a worldwide cohort of 440 patients from 365 families with NPHP-related ciliopathies, in whom both disease-causing alleles were identified. The phenotypes were ranked in the order of severity from degenerative to degenerative/dysplastic to dysplastic. A genotype of two null alleles caused a range of phenotypes, with an increasing order of severity of NPHP1 , NPHP3 , NPHP4 , NPHP5 , NPHP2 , NPHP10 , NPHP6 , to AHI1 . Only NPHP6 showed allelic influences on the phenotypes; the presence of two null mutations caused dysplastic phenotypes, whereas at least one missense allele rescued it to a milder degenerative phenotype. We also found nine novel mutations in the NPHP genes. Thus, our studies have important implications for genetic counseling and planning of renal replacement therapy.
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Pseudodominant inheritance of nephronophthisis caused by a homozygous NPHP1 deletion
Pediatric nephrology (Berlin Germany), 2011Co-Authors: Julia Hoefele, Edgar A Otto, Moumita Chaki, Susan J. Allen, Ahmet Nayir, Anita Imm, Friedhelm HildebrandtAbstract: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.
Sophie Saunier - One of the best experts on this subject based on the ideXlab platform.
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qmpsf is sensitive and specific in the detection of NPHP1 heterozygous deletions
Clinical Chemistry and Laboratory Medicine, 2017Co-Authors: Eszter Jávorszky, Sophie Saunier, Corinne Antignac, Vincent Moriniere, Andrea Kerti, Eszter Balogh, Henriett Pikó, Veronika Karcagi, Kálmán ToryAbstract:BACKGROUND Nephronophthisis, an autosomal recessive nephropathy, is responsible for 10% of childhood chronic renal failure. The deletion of its major gene, NPHP1, with a minor allele frequency of 0.24% in the general population, is the most common mutation leading to a monogenic form of childhood chronic renal failure. It is challenging to detect it in the heterozygous state. We aimed to evaluate the sensitivity and the specificity of the quantitative multiplex PCR of short fluorescent fragments (QMPSF) in its detection. METHODS After setting up the protocol of QMPSF, we validated it on 39 individuals diagnosed by multiplex ligation-dependent probe amplification (MLPA) with normal NPHP1 copy number (n=17), with heterozygous deletion (n=13, seven parents and six patients), or with homozygous deletion (n=9). To assess the rate of the deletions that arise from independent events, deleted alleles were haplotyped. RESULTS The results of QMPSF and MLPA correlated perfectly in the identification of 76 heterozygously deleted and 56 homozygously deleted exons. The inter-experimental variability of the dosage quotient obtained by QMPSF was low: control, 1.05 (median; range, 0.86-1.33, n = 102 exons); heterozygous deletion, 0.51 (0.42-0.67, n = 76 exons); homozygous deletion, 0 (0-0, n = 56 exons). All patients harboring a heterozygous deletion were found to carry a hemizygous mutation. At least 15 out of 18 deletions appeared on different haplotypes and one deletion appeared de novo. CONCLUSIONS The cost- and time-effective QMPSF has a 100% sensitivity and specificity in the detection of NPHP1 deletion. The potential de novo appearance of NPHP1 deletions makes its segregation analysis highly recommended in clinical practice.
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QMPSF is sensitive and specific in the detection of NPHP1 heterozygous deletions.
Clinical chemistry and laboratory medicine, 2017Co-Authors: Eszter Jávorszky, Sophie Saunier, Corinne Antignac, Vincent Moriniere, Andrea Kerti, Eszter Balogh, Henriett Pikó, Veronika Karcagi, Kálmán ToryAbstract:Nephronophthisis, an autosomal recessive nephropathy, is responsible for 10% of childhood chronic renal failure. The deletion of its major gene, NPHP1, with a minor allele frequency of 0.24% in the general population, is the most common mutation leading to a monogenic form of childhood chronic renal failure. It is challenging to detect it in the heterozygous state. We aimed to evaluate the sensitivity and the specificity of the quantitative multiplex PCR of short fluorescent fragments (QMPSF) in its detection. After setting up the protocol of QMPSF, we validated it on 39 individuals diagnosed by multiplex ligation-dependent probe amplification (MLPA) with normal NPHP1 copy number (n=17), with heterozygous deletion (n=13, seven parents and six patients), or with homozygous deletion (n=9). To assess the rate of the deletions that arise from independent events, deleted alleles were haplotyped. The results of QMPSF and MLPA correlated perfectly in the identification of 76 heterozygously deleted and 56 homozygously deleted exons. The inter-experimental variability of the dosage quotient obtained by QMPSF was low: control, 1.05 (median; range, 0.86-1.33, n = 102 exons); heterozygous deletion, 0.51 (0.42-0.67, n = 76 exons); homozygous deletion, 0 (0-0, n = 56 exons). All patients harboring a heterozygous deletion were found to carry a hemizygous mutation. At least 15 out of 18 deletions appeared on different haplotypes and one deletion appeared de novo. The cost- and time-effective QMPSF has a 100% sensitivity and specificity in the detection of NPHP1 deletion. The potential de novo appearance of NPHP1 deletions makes its segregation analysis highly recommended in clinical practice.
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Alteration of nephrocystins and IFT-A proteins causes similar ciliary phenotypes leading to Nephronophthisis
Cilia, 2012Co-Authors: Sophie Saunier, Thierry Blisnick, Albane A Bizet, Isabelle Perrault, Emilie Filhol, Flora Silbermann, Anthony Henneveu, Emilie Montenont, Christine Boyle-feysot, Jean-michel RozetAbstract:Nephronophtisis (NPH) is a kidney ciliopathy often associated with extra-renal defects and for which 12 genes (NPHP1-12) have been identified. NPHP1 and NPHP4 control the ciliary access at the transition zone and the velocity of some intraflagellar transport (IFT)/BBS proteins in C.elegans. Recently, in a collaborative effort, we have identified, in families with isolated NPH, mutations in TTC21B as well as in WDR19, which encode the retrograde IFT-A proteins IFT139 and IFT144, respectively. By ciliome sequencing of 1600 candidate genes from 14 NPH patients followed by Sanger sequencing of a cohort of 52 patients, we have found respectively 8 and 7 patients carrying pathogenic missense mutations in genes coding IFT-A proteins, including WDR35, TTC21B and IFT140, which could partially affect their function. Together, these results indicate that IFT-A are involved in nephronophtisis. Moreover, alteration of cilia length was observed in patient kidney, Nphp4-/- mice kidney tubules and NPHP1 or NPHP4 knockdown IMCD3 cell lines. In these cells, primary cilia present swellings at the distal region accompanied by an accumulation of IFT-B at the base and the tip, similar to what was observed in IFT-A mutants, suggesting a possible alteration of retrograde transport. Additionally, ARL13B, a small GTPase required for proper cilium shape and IFT stability, is absent along the axoneme of NPHP4-KD-IMCD cells. By controlling the entry of ciliary components at the transition zone, NPHP1 and NPHP4 may modulate IFT-A cargos thus participating in the same pathway (i.e. Wnt/PCP), alteration of which would lead to renal lesions observed in nephronophthisis.
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Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6
Human molecular genetics, 2009Co-Authors: Marion Delous, Flora Silbermann, Helori-mael Gaudé, Corinne Antignac, Rémi Salomon, Nathan E. Hellman, André Le Bivic, Sophie SaunierAbstract:Nephronophthisis (NPH) is an autosomal recessive disorder characterized by renal fibrosis, tubular basement membrane disruption and corticomedullary cyst formation leading to end-stage renal failure. The disease is caused by mutations in NPHP1-9 genes, which encode the nephrocystins, proteins localized to cell-cell junctions and centrosome/primary cilia. Here, we show that nephrocystin mRNA expression is dramatically increased during cell polarization, and shRNA-mediated knockdown of either NPHP1 or NPHP4 in MDCK cells resulted in delayed tight junction (TJ) formation, abnormal cilia formation and disorganized multi-lumen structures when grown in a three-dimensional collagen matrix. Some of these phenotypes are similar to those reported for cells depleted of the TJ proteins PALS1 or Par3, and interestingly, we demonstrate a physical interaction between these nephrocystins and PALS1 as well as their partners PATJ and Par6 and show their partial co-localization in human renal tubules. Taken together, these results demonstrate that the nephrocystins play an essential role in epithelial cell organization, suggesting a plausible mechanism by which the in vivo histopathologic features of NPH might develop.
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Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis
Kidney international, 2007Co-Authors: Matthias T.f. Wolf, John F. O'toole, Massimo Attanasio, Sophie Saunier, Rémi Salomon, N. Wanner, Ted Groshong, T. Stallmach, John A. Sayer, Rüdiger WaldherrAbstract:Joubert syndrome (JS) is an autosomal recessive disorder, consisting of mental retardation, cerebellar vermis aplasia, an irregular breathing pattern, and retinal degeneration. Nephronophthisis (NPHP) is found in 17-27% of these patients, which was designated JS type B. Mutations in four separate genes (AHI1, NPHP1, CEP290/NPHP6, and MKS3) are linked to JS. However, missense mutations in a new ciliary gene (RPGRIP1L) were found in type B patients. We analyzed a cohort of 56 patients with JS type B who were negative for mutations in three (AHI1, NPHP1, and CEP290/NPHP6) of the four genes previously linked to the syndrome. The 26 exons encoding RPGRIP1L were analyzed by means of PCR amplification, CEL I endonuclease digestion, and subsequent sequencing. Using this approach, four different mutations in the RPGRIP1L gene in five different families were identified and three were found to be novel mutations. Additionally, we verified that missense mutations are responsible for JS type B and cluster in exon 15 of the RPGRIP1L gene. Our studies confirm that a T615P mutation represents the most common mutation in the RPGRIP1L gene causing disease in about 8-10% of JS type B patients negative for NPHP1, NPHP6, or AHI1 mutations.
Susan J. Allen - One of the best experts on this subject based on the ideXlab platform.
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Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy
Human Genetics, 2013Co-Authors: Jan Halbritter, Friedhelm Hildebrandt, Daniela A. Braun, Moumita Chaki, Susan J. Allen, Jonathan D. Porath, Katrina A. Diaz, Stefan Kohl, Neveen A. Soliman, Edgar A OttoAbstract:Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal-recessive cystic kidney diseases. More than 13 genes are implicated in its pathogenesis to date, accounting for only 40 % of all cases. High-throughput mutation screenings of large patient cohorts represent a powerful tool for diagnostics and identification of novel NPHP genes. We here performed a new high-throughput mutation analysis method to study 13 established NPHP genes ( NPHP1 – NPHP13 ) in a worldwide cohort of 1,056 patients diagnosed with NPHP-RC. We first applied multiplexed PCR-based amplification using Fluidigm Access-Array™ technology followed by barcoding and next-generation resequencing on an Illumina platform. As a result, we established the molecular diagnosis in 127/1,056 independent individuals (12.0 %) and identified a single heterozygous truncating mutation in an additional 31 individuals (2.9 %). Altogether, we detected 159 different mutations in 11 out of 13 different NPHP genes, 99 of which were novel. Phenotypically most remarkable were two patients with truncating mutations in INVS/NPHP2 who did not present as infants and did not exhibit extrarenal manifestations. In addition, we present the first case of Caroli disease due to mutations in WDR19/NPHP13 and the second case ever with a recessive mutation in GLIS2/NPHP7 . This study represents the most comprehensive mutation analysis in NPHP-RC patients, identifying the largest number of novel mutations in a single study worldwide.
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clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies a single center experience
Saudi Journal of Kidney Diseases and Transplantation, 2012Co-Authors: Neveen A. Soliman, Edgar A Otto, Friedhelm Hildebrandt, Susan J. Allen, Marwa M Nabhan, Ahmed M Badr, Maha Sheba, Sawsan Fadda, Ghada Gawdat, Hassan ElkikyAbstract: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.
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Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience.
Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation Saudi Arabia, 2012Co-Authors: Neveen A. Soliman, Edgar A Otto, Friedhelm Hildebrandt, Susan J. Allen, Marwa M Nabhan, Ahmed M Badr, Maha Sheba, Sawsan Fadda, Ghada Gawdat, Hassan El-kikyAbstract: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
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Genotype–phenotype correlation in 440 patients with NPHP-related ciliopathies
Kidney international, 2011Co-Authors: Moumita Chaki, Julia Hoefele, Edgar A Otto, Gokul Ramaswami, Susan J. Allen, Sabine Janssen, Carsten Bergmann, John R. Heckenlively, Friedhelm HildebrandtAbstract:Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal failure in the first three decades of life. Mutations in 13 genes ( NPHP1 - NPHP11 , AHI1 , and CC2D2A ) cause NPHP with ubiquitous expression of the corresponding proteins consistent with the multiorgan involvement of NPHP-related diseases. The genotype–phenotype correlation in these ciliopathies can be explained by gene locus heterogeneity, allelism, and the impact of modifier genes. In some NPHP-related ciliopathies, the nature of the recessive mutations determines disease severity. In order to define the genotype–phenotype correlation more clearly, we evaluated a worldwide cohort of 440 patients from 365 families with NPHP-related ciliopathies, in whom both disease-causing alleles were identified. The phenotypes were ranked in the order of severity from degenerative to degenerative/dysplastic to dysplastic. A genotype of two null alleles caused a range of phenotypes, with an increasing order of severity of NPHP1 , NPHP3 , NPHP4 , NPHP5 , NPHP2 , NPHP10 , NPHP6 , to AHI1 . Only NPHP6 showed allelic influences on the phenotypes; the presence of two null mutations caused dysplastic phenotypes, whereas at least one missense allele rescued it to a milder degenerative phenotype. We also found nine novel mutations in the NPHP genes. Thus, our studies have important implications for genetic counseling and planning of renal replacement therapy.
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Pseudodominant inheritance of nephronophthisis caused by a homozygous NPHP1 deletion
Pediatric nephrology (Berlin Germany), 2011Co-Authors: Julia Hoefele, Edgar A Otto, Moumita Chaki, Susan J. Allen, Ahmet Nayir, Anita Imm, Friedhelm HildebrandtAbstract: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.
Corinne Antignac - One of the best experts on this subject based on the ideXlab platform.
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qmpsf is sensitive and specific in the detection of NPHP1 heterozygous deletions
Clinical Chemistry and Laboratory Medicine, 2017Co-Authors: Eszter Jávorszky, Sophie Saunier, Corinne Antignac, Vincent Moriniere, Andrea Kerti, Eszter Balogh, Henriett Pikó, Veronika Karcagi, Kálmán ToryAbstract:BACKGROUND Nephronophthisis, an autosomal recessive nephropathy, is responsible for 10% of childhood chronic renal failure. The deletion of its major gene, NPHP1, with a minor allele frequency of 0.24% in the general population, is the most common mutation leading to a monogenic form of childhood chronic renal failure. It is challenging to detect it in the heterozygous state. We aimed to evaluate the sensitivity and the specificity of the quantitative multiplex PCR of short fluorescent fragments (QMPSF) in its detection. METHODS After setting up the protocol of QMPSF, we validated it on 39 individuals diagnosed by multiplex ligation-dependent probe amplification (MLPA) with normal NPHP1 copy number (n=17), with heterozygous deletion (n=13, seven parents and six patients), or with homozygous deletion (n=9). To assess the rate of the deletions that arise from independent events, deleted alleles were haplotyped. RESULTS The results of QMPSF and MLPA correlated perfectly in the identification of 76 heterozygously deleted and 56 homozygously deleted exons. The inter-experimental variability of the dosage quotient obtained by QMPSF was low: control, 1.05 (median; range, 0.86-1.33, n = 102 exons); heterozygous deletion, 0.51 (0.42-0.67, n = 76 exons); homozygous deletion, 0 (0-0, n = 56 exons). All patients harboring a heterozygous deletion were found to carry a hemizygous mutation. At least 15 out of 18 deletions appeared on different haplotypes and one deletion appeared de novo. CONCLUSIONS The cost- and time-effective QMPSF has a 100% sensitivity and specificity in the detection of NPHP1 deletion. The potential de novo appearance of NPHP1 deletions makes its segregation analysis highly recommended in clinical practice.
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QMPSF is sensitive and specific in the detection of NPHP1 heterozygous deletions.
Clinical chemistry and laboratory medicine, 2017Co-Authors: Eszter Jávorszky, Sophie Saunier, Corinne Antignac, Vincent Moriniere, Andrea Kerti, Eszter Balogh, Henriett Pikó, Veronika Karcagi, Kálmán ToryAbstract:Nephronophthisis, an autosomal recessive nephropathy, is responsible for 10% of childhood chronic renal failure. The deletion of its major gene, NPHP1, with a minor allele frequency of 0.24% in the general population, is the most common mutation leading to a monogenic form of childhood chronic renal failure. It is challenging to detect it in the heterozygous state. We aimed to evaluate the sensitivity and the specificity of the quantitative multiplex PCR of short fluorescent fragments (QMPSF) in its detection. After setting up the protocol of QMPSF, we validated it on 39 individuals diagnosed by multiplex ligation-dependent probe amplification (MLPA) with normal NPHP1 copy number (n=17), with heterozygous deletion (n=13, seven parents and six patients), or with homozygous deletion (n=9). To assess the rate of the deletions that arise from independent events, deleted alleles were haplotyped. The results of QMPSF and MLPA correlated perfectly in the identification of 76 heterozygously deleted and 56 homozygously deleted exons. The inter-experimental variability of the dosage quotient obtained by QMPSF was low: control, 1.05 (median; range, 0.86-1.33, n = 102 exons); heterozygous deletion, 0.51 (0.42-0.67, n = 76 exons); homozygous deletion, 0 (0-0, n = 56 exons). All patients harboring a heterozygous deletion were found to carry a hemizygous mutation. At least 15 out of 18 deletions appeared on different haplotypes and one deletion appeared de novo. The cost- and time-effective QMPSF has a 100% sensitivity and specificity in the detection of NPHP1 deletion. The potential de novo appearance of NPHP1 deletions makes its segregation analysis highly recommended in clinical practice.
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Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6
Human molecular genetics, 2009Co-Authors: Marion Delous, Flora Silbermann, Helori-mael Gaudé, Corinne Antignac, Rémi Salomon, Nathan E. Hellman, André Le Bivic, Sophie SaunierAbstract:Nephronophthisis (NPH) is an autosomal recessive disorder characterized by renal fibrosis, tubular basement membrane disruption and corticomedullary cyst formation leading to end-stage renal failure. The disease is caused by mutations in NPHP1-9 genes, which encode the nephrocystins, proteins localized to cell-cell junctions and centrosome/primary cilia. Here, we show that nephrocystin mRNA expression is dramatically increased during cell polarization, and shRNA-mediated knockdown of either NPHP1 or NPHP4 in MDCK cells resulted in delayed tight junction (TJ) formation, abnormal cilia formation and disorganized multi-lumen structures when grown in a three-dimensional collagen matrix. Some of these phenotypes are similar to those reported for cells depleted of the TJ proteins PALS1 or Par3, and interestingly, we demonstrate a physical interaction between these nephrocystins and PALS1 as well as their partners PATJ and Par6 and show their partial co-localization in human renal tubules. Taken together, these results demonstrate that the nephrocystins play an essential role in epithelial cell organization, suggesting a plausible mechanism by which the in vivo histopathologic features of NPH might develop.
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Evidence of Oligogenic Inheritance in Nephronophthisis
Journal of the American Society of Nephrology : JASN, 2007Co-Authors: Julia Hoefele, John F. O'toole, Massimo Attanasio, Edgar A Otto, Matthias T.f. Wolf, Ulla T. Schultheiss, Georges Deschênes, Boris Utsch, Corinne Antignac, Friedhelm HildebrandtAbstract:Nephronophthisis is a recessive cystic renal disease that leads to end-stage renal failure in the first two decades of life. Twenty-five percent of nephronophthisis cases are caused by large homozygous deletions of NPHP1, but six genes responsible for nephronophthisis have been identified. Because oligogenic inheritance has been described for the related Bardet-Biedl syndrome, we evaluated whether mutations in more than one gene may also be detected in cases of nephronophthisis. Because the nephrocystins 1 to 4 are known to interact, we examined patients with nephronophthisis from 94 different families and sequenced all exons of the NPHP1, NPHP2, NPHP3, and NPHP4 genes. In our previous studies involving 44 families, we detected two mutations in one of the NPHP1-4 genes. Here, we detected in six families two mutations in either NPHP1, NPHP3, or NPHP4, and identified a third mutation in one of the other NPHP genes. Furthermore, we found possible digenic disease by detecting one individual who carried one mutation in NPHP2 and a second mutation in NPHP3. Finally, we detected the presence of a single mutation in nine families, suggesting that the second recessive mutation may be in another as yet unidentified NPHP gene. Our findings suggest that oligogenicity may occur in cases of nephronophthisis.
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nephronophthisis related to homozygous NPHP1 gene deletion as a cause of chronic renal failure in adults
Nephrology Dialysis Transplantation, 2006Co-Authors: Guillaume Bollee, Corinne Antignac, Rémi Salomon, Fadi Fakhouri, Alexandre Karras, Laurehelene Noel, Aude Servais, Philippe Lesavre, Vincent Moriniere, Aurelie HummelAbstract:Nephronophthisis (NPH) is an autosomal recessivenephropathy with chronic tubulointerstitial involve-ment, which represents the leading cause of end-stagerenal disease (ESRD) in children and adolescents.According to the age at onset of ESRD, three forms ofNPH have been described: infantile, juvenile (the mostfrequent) and adolescent.In the juvenile form, polyuro-polydipsia starts at4–6 years, and precedes progressive renal failure, withESRD occurring around 13 years of age [1]. Mainhistological findings are tubular atrophy with irregu-larly thickened tubular basement membranes appear-ing at an early stage, interstitial fibrosis and cysts atthe corticomedullary junction and in the medulla [2].The clinical and histological presentation is similar inthe adolescent form, with a later occurrence of ESRD(median age: 19 years). Extra-renal disorders may bepresent in the juvenile form of NPH and includemainly retinal impairment of variable severity. Theclinical and histological features of the infantile formdiffer sharply from the two others: ESRD occurs in thefirst 2 years of life, and patients usually present withenlarged kidneys and widespread cyst development[2,3]. To date, four genes implicated in juvenile oradolescent forms of NPH have been identified:NPHP1, NPHP3, NPHP4 and NPHP5. The mostfrequent genetic abnormality found in NPH is a largehomozygous deletion of the NPHP1 gene [4,5]. Thesefour genes encode proteins named nephrocystins,which have various subcellular localization, includingthe primary apical cilia, focal adhesion and adherensjunction, suggesting that they play a role in theintegrity and architecture of renal tubular epithelialcells [6]. NPHP3 mutations are responsible for theadolescent form of NPH. However, mutations in thefive known genes are found in only 50–60% of NPHcases, indicating that other genes remain to bediscovered [7].NPH is a very rare cause of ESRD in adults. Wereport four cases of NPH diagnosed in adulthood, inwhich molecular study revealed homozygous deletionof NPHP1 gene.
