The Experts below are selected from a list of 1671 Experts worldwide ranked by ideXlab platform
Edgar A Otto - One of the best experts on this subject based on the ideXlab platform.
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LETTER TO JMG Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior–Løken syndrome
2016Co-Authors: Juliana Helou, Massimo Attanasio, Edgar A Otto, Melissa A Parisi, Susan J. Allen, Ian Glass, Seema Hashmi, Elisa Fazzi, Heymut Omran, John F O’tooleAbstract:Background: Nephronophthisis (NPHP) is an autosomal reces-sive cystic kidney disease that constitutes the most common genetic cause of renal failure in the first three decades of life. Using positional cloning, six genes (NPHP1-6) have been identified as mutated in NPHP. In Joubert syndrome (JBTS), NPHP may be associated with cerebellar vermis aplasia/ hypoplasia, retinal degeneration and mental retardation. In Senior–Løken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, mutations in NPHP6/CEP290 were identified as a new cause of JBTS. Methods: Mutational analysis was performed on a worldwide cohort of 75 families with SLSN, 99 families with JBTS and 21 families with isolated nephronophthisis. Results: Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in-fram
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Pediatr Nephrol (2006) 21:32–35 DOI 10.1007/s00467-005-2054-y
2016Co-Authors: Boris Utsch, Massimo Attanasio, Edgar A Otto, John A. Sayer, Hans-christian Hennies, Rob Rodrigues, Pereira Michael Eccles, Friedhelm HildebrandtAbstract:Abstract Joubert syndrome (JBTS) is an autosomal re-cessive multisystem disease characterized by cerebellar vermis aplasia, mental retardation, muscular hypotonia, an irregular breathing pattern in the neonatal period and abnormal eye movements. Some individuals have pro-gressive renal failure characterized by nephronophthisis (NPHP) and/or retinal dystrophy. Homozygous deletions of NPHP1 on chromosome 2q13 have been identified in individuals with NPHP-associated JBTS. Recently, mu-tations in AHI1 on chromosome 6q23.3 were found in JBTS patients without NPHP. Here, by direct sequencing, we identify novel truncating mutations within AHI1 in affected patients from two families. One patient had the association of JBTS and NPHP with chronic renal failure. This is the first report of AHI1 mutations causing JBTS associated with NPHP, confirming the clinical and ge-netic heterogeneity of NPHP
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intrafamilial variability and clinical heterogeneity in two siblings with NPHP4 loss of function mutations
Journal of Molecular Biomarkers & Diagnosis, 2015Co-Authors: Marwa M Nabhan, Edgar A Otto, Friedhelm Hildebrandt, Susann Brenzinger, Sahar N Saleem, Neveen A. SolimanAbstract:Joubert syndrome–related disorders (JSRDs) are a group of clinically and genetically pleiotropic conditions that share a midbrain-hindbrain malformation, the pathognomonic molar tooth sign (MTS) visible on brain imaging, with variable involvement of other organs and systems mainly the eyes and the kidneys. Nevertheless, the definition of JSRDs remained problematical due to the extreme phenotypic heterogeneity, often with intrafamilial variability, and the significant clinical overlap among distinct forms. Here we describe two siblings with nephronophthisis (NPHP), the elder is best categorized as JSRD. Nevertheless, his younger sibling lacked the characteristic molar tooth sign; hence best categorized as NPHP- related ciliopathy. Both siblings had NPHP as the common renal phenotype, yet with variable neurological and ocular involvement. Genetic linkage and mutation analysis revealed a novel homozygous, potential loss of function mutation (c.2618dupA, pH is 873Glnfs*14) in the gene NPHP4 in both siblings. This finding extends the phenotypic spectrum associated with NPHP4 mutations, with discernible clinical heterogeneity and intrafamilial variability.
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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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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.
Friedhelm Hildebrandt - One of the best experts on this subject based on the ideXlab platform.
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Pediatr Nephrol (2006) 21:32–35 DOI 10.1007/s00467-005-2054-y
2016Co-Authors: Boris Utsch, Massimo Attanasio, Edgar A Otto, John A. Sayer, Hans-christian Hennies, Rob Rodrigues, Pereira Michael Eccles, Friedhelm HildebrandtAbstract:Abstract Joubert syndrome (JBTS) is an autosomal re-cessive multisystem disease characterized by cerebellar vermis aplasia, mental retardation, muscular hypotonia, an irregular breathing pattern in the neonatal period and abnormal eye movements. Some individuals have pro-gressive renal failure characterized by nephronophthisis (NPHP) and/or retinal dystrophy. Homozygous deletions of NPHP1 on chromosome 2q13 have been identified in individuals with NPHP-associated JBTS. Recently, mu-tations in AHI1 on chromosome 6q23.3 were found in JBTS patients without NPHP. Here, by direct sequencing, we identify novel truncating mutations within AHI1 in affected patients from two families. One patient had the association of JBTS and NPHP with chronic renal failure. This is the first report of AHI1 mutations causing JBTS associated with NPHP, confirming the clinical and ge-netic heterogeneity of NPHP
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intrafamilial variability and clinical heterogeneity in two siblings with NPHP4 loss of function mutations
Journal of Molecular Biomarkers & Diagnosis, 2015Co-Authors: Marwa M Nabhan, Edgar A Otto, Friedhelm Hildebrandt, Susann Brenzinger, Sahar N Saleem, Neveen A. SolimanAbstract:Joubert syndrome–related disorders (JSRDs) are a group of clinically and genetically pleiotropic conditions that share a midbrain-hindbrain malformation, the pathognomonic molar tooth sign (MTS) visible on brain imaging, with variable involvement of other organs and systems mainly the eyes and the kidneys. Nevertheless, the definition of JSRDs remained problematical due to the extreme phenotypic heterogeneity, often with intrafamilial variability, and the significant clinical overlap among distinct forms. Here we describe two siblings with nephronophthisis (NPHP), the elder is best categorized as JSRD. Nevertheless, his younger sibling lacked the characteristic molar tooth sign; hence best categorized as NPHP- related ciliopathy. Both siblings had NPHP as the common renal phenotype, yet with variable neurological and ocular involvement. Genetic linkage and mutation analysis revealed a novel homozygous, potential loss of function mutation (c.2618dupA, pH is 873Glnfs*14) in the gene NPHP4 in both siblings. This finding extends the phenotypic spectrum associated with NPHP4 mutations, with discernible clinical heterogeneity and intrafamilial variability.
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diverse phenotypic expression of NPHP4 mutations in four siblings
Turkish Journal of Pediatrics, 2014Co-Authors: Sevcan A Bakkaloglu, Yasar Kandur, Tugba Bedirdemirdag, Ipek Isikgonul, Friedhelm HildebrandtAbstract:Nephronophthisis (NPHP) is an autosomal recessive disease characterized by renal tubular basement membrane disruption, interstitial fibrosis and tubular cysts that progresses to end-stage kidney disease (ESKD). There are also characteristic extrarenal manifestations. Mutations of more than thirteen genes that can cause NPHP have been identified. We herein report four siblings from a consanguineous family, who carried the same NPHP4 mutations but presented with different disease phenotypes ranging from enuresis nocturna to ESKD. Diluted urine and echogenic kidneys in ultrasound examination were consistent, which is typical for 100% of the NPHP cases that have been described. Chronic kidney disease developed in the older two brothers. The observed phenotypic differences are likely to be related to environmental and epigenetic factors, oligogenic inheritance and modifier genes affecting the age of presentation of signs and symptoms. NPHP should be considered as an important cause of CKD in children, which insidiously progresses to ESKD, with no specific therapy available.
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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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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.
Kálmán Tory - One of the best experts on this subject based on the ideXlab platform.
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hypomorphic mutations in meckelin mks3 tmem67 cause nephronophthisis with liver fibrosis nphp11
Journal of Medical Genetics, 2009Co-Authors: Edgar A Otto, Massimo Attanasio, Moumita Chaki, Weibin Zhou, Matthias T F Wolf, Eric Wise, Kálmán Tory, Y. Paruchuri, Boris UtschAbstract:Background: Nephronophthisis (NPHP), a rare recessive cystic kidney disease, is the most frequent genetic cause of chronic renal failure in children and young adults. Mutations in 9 genes ( NPHP1-9 ) have been identified. NPHP can be associated with retinal degeneration (Senior-Loken syndrome), brainstem and cerebellar anomalies (Joubert syndrome), or liver fibrosis. Methods: To identify a causative gene for the subset of patients with associated liver fibrosis, we performed a genome-wide linkage search in a consanguineous family with 3 affected patients using 50K SNP microarrays and homozygosity mapping. Results: We obtained a significant maximum parametric lod score of Zmax=3.72 on chromosome 8q22 and identified a homozygous missense mutation in the gene MKS3/TMEM67 . When examining a world-wide cohort of 62 independent patients with NPHP and associated liver fibrosis we identified altogether 4 novel mutations (p.W290L, p.C615R, p.G821S, and p.G821R) in 5 of them. Mutations of MKS3/TMEM67 , found recently in Meckel-Gruber syndrome (MKS) type 3 and Joubert syndrome (JBTS) type 6 are predominantly truncating mutations. In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations. This suggests that they may represent hypomorphic alleles, leading to a milder phenotype compared with the more severe MKS or JBTS phenotype. Additionally, mutation analysis for MKS3/TMEM67 in 120 patients with JBTS yielded 7 different (4 novel) mutations in 5 patients, 4 of which presented also with congenital liver fibrosis. Conclusions: Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11). This is the first report of MKS3 mutations in patients with no vermian agenesis and without neurological signs. Thus NPHP, JBTS, and MKS represent allelic disorders.
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The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome
Nature Genetics, 2007Co-Authors: Marion Delous, Rémi Salomon, Kálmán Tory, Tiphanie Lacoste, Lekbir Baala, Christine Laclef, Jeanette Vierkotten, Christelle Golzio, Laurianne Besse, Catherine OzilouAbstract:Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L ( KIAA1005 ) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l ( Ftm ) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4 , known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder.
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high nphp1 and nphp6 mutation rate in patients with joubert syndrome and nephronophthisis potential epistatic effect of nphp6 and ahi1 mutations in patients with nphp1 mutations
Journal of The American Society of Nephrology, 2007Co-Authors: Kálmán Tory, Vincent Moriniere, Tiphanie Lacoste, Lydie Burglen, Nathalie Boddaert, Marie Alice Macher, Brigitte Llanas, Hubert Nivet, Albert Bensman, Patrick NiaudetAbstract: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 P 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.
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High NPHP1 and NPHP6 Mutation Rate in Patients with Joubert Syndrome and Nephronophthisis: Potential Epistatic Effect of NPHP6 and AHI1 Mutations in Patients with NPHP1 Mutations
Journal of the American Society of Nephrology : JASN, 2007Co-Authors: Kálmán Tory, Vincent Moriniere, Tiphanie Lacoste, Lydie Burglen, Nathalie Boddaert, Marie Alice Macher, Brigitte Llanas, Hubert Nivet, Albert Bensman, Patrick NiaudetAbstract: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.
Massimo Attanasio - One of the best experts on this subject based on the ideXlab platform.
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LETTER TO JMG Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior–Løken syndrome
2016Co-Authors: Juliana Helou, Massimo Attanasio, Edgar A Otto, Melissa A Parisi, Susan J. Allen, Ian Glass, Seema Hashmi, Elisa Fazzi, Heymut Omran, John F O’tooleAbstract:Background: Nephronophthisis (NPHP) is an autosomal reces-sive cystic kidney disease that constitutes the most common genetic cause of renal failure in the first three decades of life. Using positional cloning, six genes (NPHP1-6) have been identified as mutated in NPHP. In Joubert syndrome (JBTS), NPHP may be associated with cerebellar vermis aplasia/ hypoplasia, retinal degeneration and mental retardation. In Senior–Løken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, mutations in NPHP6/CEP290 were identified as a new cause of JBTS. Methods: Mutational analysis was performed on a worldwide cohort of 75 families with SLSN, 99 families with JBTS and 21 families with isolated nephronophthisis. Results: Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in-fram
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Pediatr Nephrol (2006) 21:32–35 DOI 10.1007/s00467-005-2054-y
2016Co-Authors: Boris Utsch, Massimo Attanasio, Edgar A Otto, John A. Sayer, Hans-christian Hennies, Rob Rodrigues, Pereira Michael Eccles, Friedhelm HildebrandtAbstract:Abstract Joubert syndrome (JBTS) is an autosomal re-cessive multisystem disease characterized by cerebellar vermis aplasia, mental retardation, muscular hypotonia, an irregular breathing pattern in the neonatal period and abnormal eye movements. Some individuals have pro-gressive renal failure characterized by nephronophthisis (NPHP) and/or retinal dystrophy. Homozygous deletions of NPHP1 on chromosome 2q13 have been identified in individuals with NPHP-associated JBTS. Recently, mu-tations in AHI1 on chromosome 6q23.3 were found in JBTS patients without NPHP. Here, by direct sequencing, we identify novel truncating mutations within AHI1 in affected patients from two families. One patient had the association of JBTS and NPHP with chronic renal failure. This is the first report of AHI1 mutations causing JBTS associated with NPHP, confirming the clinical and ge-netic heterogeneity of NPHP
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hypomorphic mutations in meckelin mks3 tmem67 cause nephronophthisis with liver fibrosis nphp11
Journal of Medical Genetics, 2009Co-Authors: Edgar A Otto, Massimo Attanasio, Moumita Chaki, Weibin Zhou, Matthias T F Wolf, Eric Wise, Kálmán Tory, Y. Paruchuri, Boris UtschAbstract:Background: Nephronophthisis (NPHP), a rare recessive cystic kidney disease, is the most frequent genetic cause of chronic renal failure in children and young adults. Mutations in 9 genes ( NPHP1-9 ) have been identified. NPHP can be associated with retinal degeneration (Senior-Loken syndrome), brainstem and cerebellar anomalies (Joubert syndrome), or liver fibrosis. Methods: To identify a causative gene for the subset of patients with associated liver fibrosis, we performed a genome-wide linkage search in a consanguineous family with 3 affected patients using 50K SNP microarrays and homozygosity mapping. Results: We obtained a significant maximum parametric lod score of Zmax=3.72 on chromosome 8q22 and identified a homozygous missense mutation in the gene MKS3/TMEM67 . When examining a world-wide cohort of 62 independent patients with NPHP and associated liver fibrosis we identified altogether 4 novel mutations (p.W290L, p.C615R, p.G821S, and p.G821R) in 5 of them. Mutations of MKS3/TMEM67 , found recently in Meckel-Gruber syndrome (MKS) type 3 and Joubert syndrome (JBTS) type 6 are predominantly truncating mutations. In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations. This suggests that they may represent hypomorphic alleles, leading to a milder phenotype compared with the more severe MKS or JBTS phenotype. Additionally, mutation analysis for MKS3/TMEM67 in 120 patients with JBTS yielded 7 different (4 novel) mutations in 5 patients, 4 of which presented also with congenital liver fibrosis. Conclusions: Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11). This is the first report of MKS3 mutations in patients with no vermian agenesis and without neurological signs. Thus NPHP, JBTS, and MKS represent allelic disorders.
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Mutation analysis in nephronophthisis using a combined approach of homozygosity mapping, CEL I endonuclease cleavage, and direct sequencing
Human mutation, 2008Co-Authors: Edgar A Otto, John F. O'toole, Massimo Attanasio, Susan J. Allen, Weibin Zhou, Matthias T F Wolf, Juliana Helou, Eric Wise, Shazia Ashraf, Friedhelm HildebrandtAbstract:Nephronophthisis (NPHP), an autosomal recessive kidney disease, is the most frequent genetic cause of chronic renal failure in the first three decades of life. Mutations in eight genes (NPHP1-8) have been identified. We here describe a combined approach for mutation screening of NPHP1, NPHP2, NPHP3, NPHP4, and NPHP5 in a worldwide cohort of 470 unrelated patients with NPHP. First, homozygous NPHP1 deletions were detected in 97 patients (21%) by multiplex PCR. Second, 25 patients with infantile NPHP were screened for mutations in inversin (NPHP2/INVS). We detected a novel compound heterozygous frameshift mutation (p.[Q485fs]+[R687fs]), and a homozygous nonsense mutation (p.R899X). Third, 37 patients presenting with NPHP and retinitis pigmentosa (Senior-Loken syndrome [SLS]) were screened for NPHP5/IQCB1 mutations by direct sequencing. We discovered five different (three novel) homozygous premature termination codon (PTC) mutations (p.F142fsX; p.R461X; p.R489X; p.W444X; and c.488-1G>A). The remaining 366 patients were further investigated for mutations in NPHP1, NPHP3, and NPHP4. We applied a "homozygosity only" strategy and typed three highly polymorphic microsatellite markers at the respective loci. A total of 32, eight, and 14 patients showed homozygosity, and were screened by heteroduplex crude celery extract (CEL I) endonuclease digests. The sensitivity of CEL I was established as 92%, as it detected 73 out of 79 different known mutations simply on agarose gels. A total of 10 novel PTC mutations were found in NPHP1 (p.P186fs, p.R347X, p.V492fs, p.Y509X, and c.1884+1G>A), in NPHP3 (c.3812+2T>C and p.R1259X), and in NPHP4 (p.R59X, p.T1004fs, and p.V1091fs). The combined homozygosity mapping and CEL I endonuclease mutation analysis approach allowed us to identify rare mutations in a large cohort of patients at low cost.
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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.
Rémi Salomon - One of the best experts on this subject based on the ideXlab platform.
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control of the wnt pathways by nephrocystin 4 is required for morphogenesis of the zebrafish pronephros
Human Molecular Genetics, 2011Co-Authors: Celine Burckle, Helori-mael Gaudé, Rémi Salomon, Christine Vesque, Flora Silbermann, Cecile JeanpierreAbstract:Nephronophthisis is a hereditary nephropathy characterized by interstitial fibrosis and cyst formation. It is caused by mutations in NPHP genes encoding the ciliary proteins, nephrocystins. In this paper, we investigate the function of nephrocystin-4, the product of the NPHP4 gene, in vivo by morpholino-mediated knockdown in zebrafish and in vitro in mammalian kidney cells. Depletion of nephrocystin-4 results in convergence and extension defects, impaired laterality, retinal anomalies and pronephric cysts associated with alterations in early cloacal morphogenesis. These defects are accompanied by abnormal ciliogenesis in the cloaca and in the laterality organ. We show that nephrocystin-4 is required for the elongation of the caudal pronephric primordium and for the regulation of cell rearrangements during cloaca morphogenesis. Moreover, depletion of either inversin, the product of the nphp2 gene, or of the Wnt-planar cell polarity (PCP) pathway component prickle2 increases the proportion of cyst formation in NPHP4-depleted embryos. Nephrocystin-4 represses the Wnt-b-catenin pathway in the zebrafish cloaca and in mammalian kidney cells in culture. In these cells, nephrocystin-4 interacts with inversin and dishevelled, and regulates dishevelled stability and subcellular localization. Our data point to a function of nephrocystin-4 in a tight regulation of the Wnt-b-catenin and Wnt-PCP pathways, in particular during morphogenesis of the zebrafish pronephros. Moreover, they highlight common signalling functions for inversin and nephrocystin-4, suggesting that these two nephrocystins are involved in common physiopathological mechanisms.
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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.
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The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome
Nature Genetics, 2007Co-Authors: Marion Delous, Rémi Salomon, Kálmán Tory, Tiphanie Lacoste, Lekbir Baala, Christine Laclef, Jeanette Vierkotten, Christelle Golzio, Laurianne Besse, Catherine OzilouAbstract:Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L ( KIAA1005 ) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l ( Ftm ) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4 , known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder.
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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.
