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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, Edgar A Otto, Melissa A Parisi, Susan J. Allen, Elisa Fazzi, Ian Glass, Seema Hashmi, 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, Edgar A Otto, 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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mutation analysis of 18 Nephronophthisis associated ciliopathy disease genes using a dna pooling and next generation sequencing strategy
Journal of Medical Genetics, 2011Co-Authors: Edgar A Otto, Gokul Ramaswami, Moumita Chaki, Susan J. Allen, Sabine Janssen, Weibin Zhou, Rannar Airik, Toby W Hurd, Amiya K Ghosh, Matthias T F WolfAbstract:Background Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic kidney diseases that includes Nephronophthisis (NPHP), Senior-Loken syndrome (SLS), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). To date, causative mutations in NPHP-AC have been described for 18 different genes, rendering mutation analysis tedious and expensive. To overcome the broad genetic locus heterogeneity, a strategy of DNA pooling with consecutive massively parallel resequencing (MPR) was devised. Methods In 120 patients with severe NPHP-AC phenotypes, five pools of genomic DNA with 24 patients each were prepared which were used as templates in order to PCR amplify all 376 exons of 18 NPHP-AC genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, TMEM67, INPP5E, TMEM216, AHI1, ARL13B, CC2D2A, TTC21B, MKS1, and XPNPEP3). PCR products were then subjected to MPR on an Illumina Genome-Analyser and mutations were subsequently assigned to their respective mutation carrier via CEL I endonuclease based heteroduplex screening and confirmed by Sanger sequencing. Results For proof of principle, DNA from patients with known mutations was used and detection of 22 out of 24 different alleles (92% sensitivity) was demonstrated. MPR led to the molecular diagnosis in 30/120 patients (25%) and 54 pathogenic mutations (27 novel) were identified in seven different NPHP-AC genes. Additionally, in 24 patients only single heterozygous variants of unknown significance were found. Conclusions The combined approach of DNA pooling followed by MPR strongly facilitates mutation analysis in broadly heterogeneous single gene disorders. The lack of mutations in 75% of patients in this cohort indicates further extensive heterogeneity in NPHP-AC.
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ahi1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in Nephronophthisis
Nature Genetics, 2010Co-Authors: Carrie M Louie, Andrew M Schlossman, Madeline A Lancaster, Vanda S Lopes, Gianluca Caridi, Edgar A Otto, Andreas Kispert, Michael LeitgesAbstract:Degeneration of photoreceptors is a common feature of ciliopathies, owing to the importance of the specialized ciliary structure of these cells. Mutations in AHI1, which encodes a cilium-localized protein, have been shown to cause a form of Joubert syndrome that is highly penetrant for retinal degeneration 1,2 . We show that Ahi1-null mice fail to form retinal outer segments and have abnormal distribution of opsin throughout their photoreceptors. Apoptotic cell death of photoreceptors occurs rapidly between 2 and 4 weeks of age in these mice and is significantly (P = 0.00175 and 0.00613) delayed by a reduced dosage of opsin. This phenotype also shows dosage-sensitive genetic interactions with Nphp1, another ciliopathy-related gene. Although it is not a primary cause of retinal blindness in humans, we show that an allele of AHI1 is associated with a more than sevenfold increase in relative risk of retinal degeneration within a cohort of individuals with the hereditary kidney disease Nephronophthisis. Our data support context-specific roles for AHI1 as a contributor to retinopathy and show that AHI1 may explain a proportion of the variability in retinal phenotypes observed in Nephronophthisis.
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Nephronophthisis disease mechanisms of a ciliopathy
Journal of The American Society of Nephrology, 2009Co-Authors: Friedhelm Hildebrandt, Massimo Attanasio, Edgar A OttoAbstract:Nephronophthisis (NPHP), a recessive cystic kidney disease, is the most frequent genetic cause of end-stage kidney disease in children and young adults. Positional cloning of nine genes (NPHP1-9) and functional characterization of their encoded proteins (nephrocystins) has contributed to a unifying theory that defines cystic kidney diseases as “ciliopathies”. The theory is based on the finding that all proteins mutated in cystic kidney diseases of humans or animal models are expressed in primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensory organelles that connect mechanosensory, visual, and other stimuli to mechanisms of epithelial cell polarity and cell cycle control. Mutations in NPHP genes cause defects in signaling mechanisms that involve the non-canonical Wnt signaling pathway and the sonic hedgehog signaling pathway, resulting in defects of planar cell polarity and tissue maintenance. The ciliary theory explains the multiple organ involvement in NPHP, which includes retinal degeneration, cerebellar hypoplasia, liver fibrosis, situs inversus, and mental retardation. Positional cloning of dozens of unknown genes that cause NPHP will elucidate further signaling mechanisms involved. Nephrocystins are highly conserved in evolution, thus allowing the use of animal models to develop future therapeutic approaches.
Friedhelm Hildebrandt - One of the best experts on this subject based on the ideXlab platform.
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roscovitine blocks collecting duct cyst growth in cep164 deficient kidneys
Kidney International, 2019Co-Authors: Rannar Airik, Merlin Airik, Markus Schueler, Carlton M Bates, Friedhelm HildebrandtAbstract:Nephronophthisis is an autosomal recessive kidney disease with high genetic heterogeneity. Understanding the functions of the individual genes contributing to this disease is critical for delineating the pathomechanisms of this disorder. Here, we investigated kidney function of a novel gene associated with Nephronophthisis, CEP164, coding a centriolar distal appendage protein, using a Cep164 knockout mouse model. Collecting duct-specific deletion of Cep164 abolished primary cilia from the collecting duct epithelium and led to rapid postnatal cyst growth in the kidneys. Cell cycle and biochemical studies revealed that tubular hyperproliferation is the primary mechanism that drives cystogenesis in the kidneys of these mice. Administration of roscovitine, a cell cycle inhibitor, blocked cyst growth in the cortical collecting ducts and preserved kidney parenchyma in Cep164 knockout mice. Thus, our findings provide evidence that therapeutic modulation of cell cycle activity can be an effective approach to prevent cyst progression in the kidney.
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Pediatr Nephrol (2006) 21:32–35 DOI 10.1007/s00467-005-2054-y
2016Co-Authors: Boris Utsch, Edgar A Otto, 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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Nephronophthisis disease mechanisms of a ciliopathy
Journal of The American Society of Nephrology, 2009Co-Authors: Friedhelm Hildebrandt, Massimo Attanasio, Edgar A OttoAbstract:Nephronophthisis (NPHP), a recessive cystic kidney disease, is the most frequent genetic cause of end-stage kidney disease in children and young adults. Positional cloning of nine genes (NPHP1-9) and functional characterization of their encoded proteins (nephrocystins) has contributed to a unifying theory that defines cystic kidney diseases as “ciliopathies”. The theory is based on the finding that all proteins mutated in cystic kidney diseases of humans or animal models are expressed in primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensory organelles that connect mechanosensory, visual, and other stimuli to mechanisms of epithelial cell polarity and cell cycle control. Mutations in NPHP genes cause defects in signaling mechanisms that involve the non-canonical Wnt signaling pathway and the sonic hedgehog signaling pathway, resulting in defects of planar cell polarity and tissue maintenance. The ciliary theory explains the multiple organ involvement in NPHP, which includes retinal degeneration, cerebellar hypoplasia, liver fibrosis, situs inversus, and mental retardation. Positional cloning of dozens of unknown genes that cause NPHP will elucidate further signaling mechanisms involved. Nephrocystins are highly conserved in evolution, thus allowing the use of animal models to develop future therapeutic approaches.
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Identification of the first AHI1 gene mutations in Nephronophthisis-associated Joubert syndrome
Pediatric Nephrology, 2006Co-Authors: Boris Utsch, Edgar A Otto, Rob Rodrigues Pereira, Michael Eccles, Hans-christian Hennies, Friedhelm HildebrandtAbstract:Joubert syndrome (JBTS) is an autosomal recessive 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 progressive 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, mutations 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 genetic heterogeneity of NPHP.
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New insights: Nephronophthisis-medullary cystic kidney disease.
Pediatric nephrology (Berlin Germany), 2001Co-Authors: Friedhelm Hildebrandt, H. OmramAbstract:Nephronophthisis (NPH) and medullary cystic kidney disease (MCKD) constitute a group of renal cystic diseases, which share a common characteristic renal histologic triad of tubular basement membrane disintegration, tubular atrophy with cyst development, and interstitial cell infiltration with fibrosis. The different disease variants lead to chronic renal failure with onset at characteristic age ranges for recessive NPH and dominant MCKD. There is extensive gene locus heterogeneity with at least three different loci for Nephronophthisis (NPHP1, NPHP2, and NPHP3) and two different loci for MCKD (MCKD1 and MCKD2). Juvenile Nephronophthisis, in addition, can be associated with extrarenal organ involvement. We have identified by positional cloning the gene (NPHP1) for juvenile Nephronophthisis (NPH1), as a first step towards understanding the pathogenesis of this disease group. Its gene product, nephrocystin, is a novel protein, which contains a src-homology 3 (SH3) domain. We put forward a hypothesis that the pathogenesis of NPH might be related to signaling processes at focal adhesions (the contact points between cells and extracellular matrix) and/or adherens junctions (the contact points between cells).
Melissa A Parisi - One of the best experts on this subject based on the ideXlab platform.
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the molecular genetics of joubert syndrome and related ciliopathies the challenges of genetic and phenotypic heterogeneity
Translational Science of Rare Diseases, 2019Co-Authors: Melissa A ParisiAbstract:Joubert syndrome (JS; MIM PS213300) is a rare, typically autosomal recessive disorder characterized by cerebellar vermis hypoplasia and a distinctive malformation of the cerebellum and brainstem identified as the "molar tooth sign" on brain MRI. Other universal features include hypotonia with later ataxia and intellectual disability/developmental delay, with additional features consisting of oculomotor apraxia and abnormal respiratory pattern. Notably, other, more variable features include renal cystic disease, typically Nephronophthisis, retinal dystrophy, and congenital hepatic fibrosis; skeletal changes such as polydactyly and findings consistent with short-rib skeletal dysplasias are also seen in many subjects. These pleiotropic features are typical of a number of disorders of the primary cilium, and make the identification of causal genes challenging given the significant overlap between JS and other ciliopathy conditions such as Nephronophthisis and Meckel, Bardet-Biedl, and COACH syndromes. This review will describe the features of JS, characterize the 35 known genes associated with the condition, and describe some of the genetic conundrums of JS, such as the heterogeneity of founder effects, lack of genotype-phenotype correlations, and role of genetic modifiers. Finally, aspects of JS and related ciliopathies that may pave the way for development of therapeutic interventions, including gene therapy, will be described.
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Prospective Evaluation of Kidney Disease in Joubert Syndrome
Clinical journal of the American Society of Nephrology : CJASN, 2017Co-Authors: Leah R. Fleming, Ian A. Glass, Dan Doherty, Melissa A Parisi, Joy Bryant, Roxanne Fischer, Baris Turkbey, Peter L. Choyke, Kailash Daryanani, Meghana VemulapalliAbstract:Background and objectives Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center. Design, setting, participants, & measurements We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing. Results Patients were ages 0.6–36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67, C5orf42, CC2D2A, CEP290, AHI1, and KIAA0586. Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included Nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/Nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (n=13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old). Conclusions Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in CEP290, TMEM67, and AHI1. Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease–like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype.
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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, Edgar A Otto, Melissa A Parisi, Susan J. Allen, Elisa Fazzi, Ian Glass, Seema Hashmi, 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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clinical and molecular features of joubert syndrome and related disorders
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2009Co-Authors: Melissa A ParisiAbstract:Joubert syndrome (JBTS; OMIM 213300) is a rare, autosomal recessive disorder characterized by a specific congenital malformation of the hindbrain and a broad spectrum of other phenotypic findings that is now known to be caused by defects in the structure and/or function of the primary cilium. The complex hindbrain malformation that is characteristic of JBTS can be identified on axial magnetic resonance imaging and is known as the molar tooth sign (MTS); other diagnostic criteria include intellectual disability, hypotonia, and often, abnormal respiratory pattern and/or abnormal eye movements. In addition, a broad spectrum of other anomalies characterize Joubert syndrome and related disorders (JSRD), and may include retinal dystrophy, ocular coloboma, oral frenulae and tongue tumors, polydactyly, cystic renal disease (including cystic dysplasia or juvenile Nephronophthisis), and congenital hepatic fibrosis. The clinical course can be variable, but most children with this condition survive infancy to reach adulthood. At least eight genes cause JSRD, with some genotype-phenotype correlations emerging, including the association between mutations in the MKS3 gene and hepatic fibrosis characteristic of the JSRD subtype known as COACH syndrome. Several of the causative genes for JSRD are implicated in other ciliary disorders, such as juvenile Nephronophthisis and Meckel syndrome, illustrating the close association between these conditions and their overlapping clinical features that reflect a shared etiology involving the primary cilium.
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mks3 related ciliopathy with features of autosomal recessive polycystic kidney disease Nephronophthisis and joubert syndrome
The Journal of Pediatrics, 2009Co-Authors: Meral Gunayaygun, Dan Doherty, Melissa A Parisi, Baris Turkbey, Peter L. Choyke, Maya Tuchman, Ekaterini Tsilou, David E Kleiner, Marjan Huizing, Lisa M GuaywoodfordAbstract:Objectives To describe 3 children with mutations in a Meckel syndrome gene ( MKS3 ), with features of autosomal recessive polycystic kidney disease (ARPKD), Nephronophthisis, and Joubert syndrome (JS). Studydesign Biochemical evaluations, magnetic resonance and ultrasound imaging, electroretinograms, IQ testing, and sequence analysis of the PKHD1 and MKS3 genes were performed. Functional consequences of the MKS3 mutations were evaluated by cDNA sequencing and transfection studies with constructs of meckelin, the protein product of MKS3. Results These 3 children with MKS3 mutations had features typical of ARPKD, that is, enlarged, diffusely microcystic kidneys and early-onset severe hypertension. They also exhibited early-onset chronic anemia, a feature of Nephronophthisis, and speech and oculomotor apraxia, suggestive of JS. Magnetic resonance imaging of the brain, originally interpreted as normal, revealed midbrain and cerebellar abnormalities in the spectrum of the "molar tooth sign" that characterizes JS. Conclusions These findings expand the phenotypes associated with MKS3 mutations. MKS3 -related ciliopathies should be considered in patients with an ARPKD-like phenotype, especially in the presence of speech and oculomotor apraxia. In such patients, careful expert evaluation of the brain images can be beneficial because the brain malformations can be subtle.
Martin R Pollak - One of the best experts on this subject based on the ideXlab platform.
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novel mutations in nphp4 in a consanguineous family with histological findings of focal segmental glomerulosclerosis
American Journal of Kidney Diseases, 2007Co-Authors: Kirtida Mistry, James Ireland, Joel M Henderson, Martin R PollakAbstract:Nephronophthisis is a form of autosomal recessive hereditary cystic kidney disease that typically progresses to end-stage renal disease by early adulthood. Conversely, focal segmental glomerulosclerosis is a histological glomerular phenotype that can be familial, primary (idiopathic), or secondary to a multitude of pathological processes affecting the kidney, including such tubulointerstitial diseases as Nephronophthisis. Mutations in 6 distinct Nephronophthisis genes have been described to date. We describe a consanguineous Filipino family with 2 novel sequence variants in the NPHP4 gene. Affected individuals presented with end-stage renal disease and histological features of focal segmental glomerulosclerosis on biopsy. They also had atypical radiological findings, making the clinical diagnosis of the genetic syndrome difficult. Furthermore, although ocular abnormalities and hearing loss were described previously, this is the first report of hepatic disease in patients with mutations in NPHP4. The diagnosis of Nephronophthisis was made by means of mutational analysis of the NPHP4 gene after isolation of a region of homozygosity in affected individuals by using whole-genome single-nucleotide polymorphism analysis. Because establishment of the correct diagnosis has implications for therapeutic interventions, prognosis, and, in the case of heritable diseases, appropriate genetic counseling for affected individuals and their families, this report emphasizes the importance of obtaining meticulous clinical information, considering alternative diagnoses, and, when possible, performing genetic evaluation to confirm the diagnosis. We outline an approach to patients with hereditary kidney disease, focusing specifically on the molecular genetic techniques available to evaluate such families and determine a chromosomal region of interest and, subsequently, the diagnosis.
Juliana Helou - 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, Edgar A Otto, Melissa A Parisi, Susan J. Allen, Elisa Fazzi, Ian Glass, Seema Hashmi, 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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mutation analysis of nphp6 cep290 in patients with joubert syndrome and senior loken syndrome
Journal of Medical Genetics, 2007Co-Authors: Juliana Helou, Ian A. Glass, Edgar A Otto, Melissa A Parisi, Susan J. Allen, Boris Utsch, Elisa Fazzi, Seema Hashmi, Heymut OmranAbstract:ABSTRACT Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease, which constitutes the most frequent genetic cause of renal failure in the first three decades of life. By positional cloning, 6 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-Loken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, we identified mutations in NPHP6/CEP290 as a new cause of JBTS. Here we performed mutational analysis in a worldwide cohort of 75 families with SLSN, 99 families with JBTS, and 21 families with isolated Nephronophthisis. We identified 6 novel and 6 known truncating mutations, 1 known missense mutation and 1 novel 3 base pair in-frame deletion in a total of 7 families with JBTS, 2 families with SLSN, and 1 family with isolated NPHP.
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mutation analysis of nphp6 cep290 in patients with joubert syndrome ana senior loken syndrome
Journal of Medical Genetics, 2007Co-Authors: Juliana Helou, Ian A. Glass, Edgar A Otto, Melissa A Parisi, Susan J. Allen, Boris Utsch, Elisa Fazzi, Massimo Attanasio, Seema Hashmi, Heymut OmranAbstract:ABSTRACT Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease, which constitutes the most frequent genetic cause of renal failure in the first three decades of life. By positional cloning, 6 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-Loken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, we identified mutations in NPHP6/CEP290 as a new cause of JBTS. Here we performed mutational analysis in a worldwide cohort of 75 families with SLSN, 99 families with JBTS, and 21 families with isolated Nephronophthisis. We identified 6 novel and 6 known truncating mutations, 1 known missense mutation and 1 novel 3 base pair in-frame deletion in a total of 7 families with JBTS, 2 families with SLSN, and 1 family with isolated NPHP.
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the centrosomal protein nephrocystin 6 is mutated in joubert syndrome and activates transcription factor atf4
Nature Genetics, 2006Co-Authors: John F Otoole, Edgar A Otto, John A. Sayer, Hans-christian Hennies, Gudrun Nürnberg, Christian Becker, Michael A Kennedy, Juliana HelouAbstract:The molecular basis of Nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing Nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.