1,147 results on '"nephronophthisis"'
Search Results
2. Genome sequencing identifies biallelic variants in SCLT1 in a patient with syndromic nephronophthisis: Reflections on the SCLT1‐related ciliopathy spectrum.
- Author
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Gillesse, E., Wade, A., Parboosingh, J. S., Au, P. Y. B., Bernier, F. P., Lamont, R. E., and Innes, A. M.
- Abstract
Ciliopathies represent a major category of rare multisystem disease. Arriving at a specific diagnosis for a given patient is challenged by the significant genetic and clinical heterogeneity of these conditions. We report the outcome of the diagnostic odyssey of a child with obesity, renal, and retinal disease. Genome sequencing identified biallelic splice site variants in sodium channel and clathrin linker 1 (SCLT1), an emerging ciliopathy gene. We review the literature on all patients reported with biallelic SCLT1 variants highlighting a frequent clinical presentation that overlaps Bardet–Biedl and Senior–Loken syndromes. We also discuss current concepts in syndrome designation in light of these data. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Case report of a child with nephronophthisis from South Africa
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Rajendra Bhimma, Edgar Jembere, and Sudesh Hariparshad
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Nephronophthisis ,Chronic kidney failure ,Children ,Genetic testing ,Pediatrics ,RJ1-570 - Abstract
Abstract Background Nephronophthisis (NPHP) is an autosomal recessive disorder with a subset of patients presenting with extrarenal manifestations such as retinal degeneration, cerebella ataxia, liver fibrosis, skeletal abnormalities, cardiac malformations, and lung bronchiectasis. However, the involvement of other organ systems has also been documented. Extrarenal manifestations occur in approximately 10–20% of patients. In developed countries, it has been reported as one of the most common causes of monogenic chronic kidney failure (CKF) during the first three decades of life, with more than 25 genes associated with this condition. The current treatment options for managing NPHP include supportive care, management of complications, and kidney replacement therapy when necessary. The index patient is a 10-year-old Caucasian female who presented with recurrent attacks of abdominal pain. Her elder sister, TN, who was 17 years old, was diagnosed with CKF and noted to have persistently elevated liver enzymes (gamma-glutamyl transferase, alanine, and aspartate transaminases). Following genetic testing, her elder sister was shown to have Nephronophthisis Type 3, and a liver biopsy showed early fibrotic changes. Subsequent genetic testing confirmed the index patient as having NPHP Type 3. A kidney biopsy showed focal sclerosed glomeruli with patchy areas of tubular atrophy and related tubulointerstitial changes in keeping with NPHP. We present the first confirmatory case of NPHP from South Africa based on histopathology and genetic testing in a 10-year-old Caucasian female who presented with recurrent attacks of abdominal pain, whose elder sister also presented with CKF and early liver fibrosis, confirmed on biopsy and genetic testing. Conclusion In low-middle-income countries, genetic testing should be undertaken whenever possible to confirm the diagnosis of NPHP, especially in those with a suggestive biopsy or if there is CKF of unknown aetiology with or without extra-renal manifestations.
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- 2024
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- View/download PDF
4. Patient-derived and gene-edited pluripotent stem cells lacking NPHP1 recapitulate juvenile nephronophthisis in abnormalities of primary cilia and renal cyst formation.
- Author
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Yutaka Arai, Hidenori Ito, Tomoya Shimizu, Yuzuno Shimoda, Dan Song, Mami Matsuo-Takasaki, Tadayoshi Hayata, and Yohei Hayashi
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PLURIPOTENT stem cells ,CYSTIC kidney disease ,CILIA & ciliary motion ,RENAL fibrosis ,KIDNEY failure ,PEDIATRIC nephrology ,KIDNEY diseases - Abstract
Juvenile nephronophthisis is an inherited renal ciliopathy with cystic kidney disease, renal fibrosis, and end-stage renal failure in children and young adults. Mutations in the NPHP1 gene encoding nephrocystin-1 protein have been identified as the most frequently responsible gene and cause the formation of cysts in the renal medulla. The molecular pathogenesis of juvenile nephronophthisis remains elusive, and no effective medicines to prevent end-stage renal failure exist even today. No human cellular models have been available yet. Here, we report a first disease model of juvenile nephronophthisis using patient-derived and gene-edited human induced pluripotent stem cells (hiPSCs) and kidney organoids derived from these hiPSCs. We established NPHP1-overexpressing hiPSCs from patient-derived hiPSCs and NPHP1-deficient hiPSCs from healthy donor hiPSCs. Comparing these series of hiPSCs, we found abnormalities in primary cilia associated with NPHP1 deficiency in hiPSCs. Kidney organoids generated from the hiPSCs lacking NPHP1 formed renal cysts frequently in suspension culture with constant rotation. This cyst formation in patient-derived kidney organoids was rescued by overexpression of NPHP1. Transcriptome analysis on these kidney organoids revealed that loss of NPHP1 caused lower expression of genes related to primary cilia in epithelial cells and higher expression of genes related to the cell cycle. These findings suggested the relationship between abnormality in primary cilia induced by NPHP1 loss and abnormal proliferative characteristics in the formation of renal cysts. These findings demonstrated that hiPSC-based systematic disease modeling of juvenile nephronophthisis contributed to elucidating the molecular pathogenesis and developing new therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
5. Case report of a child with nephronophthisis from South Africa.
- Author
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Bhimma, Rajendra, Jembere, Edgar, and Hariparshad, Sudesh
- Subjects
CHRONIC kidney failure ,HEPATIC fibrosis ,RENAL replacement therapy ,BRONCHIECTASIS ,GENETIC testing ,RENAL biopsy - Abstract
Background: Nephronophthisis (NPHP) is an autosomal recessive disorder with a subset of patients presenting with extrarenal manifestations such as retinal degeneration, cerebella ataxia, liver fibrosis, skeletal abnormalities, cardiac malformations, and lung bronchiectasis. However, the involvement of other organ systems has also been documented. Extrarenal manifestations occur in approximately 10–20% of patients. In developed countries, it has been reported as one of the most common causes of monogenic chronic kidney failure (CKF) during the first three decades of life, with more than 25 genes associated with this condition. The current treatment options for managing NPHP include supportive care, management of complications, and kidney replacement therapy when necessary. The index patient is a 10-year-old Caucasian female who presented with recurrent attacks of abdominal pain. Her elder sister, TN, who was 17 years old, was diagnosed with CKF and noted to have persistently elevated liver enzymes (gamma-glutamyl transferase, alanine, and aspartate transaminases). Following genetic testing, her elder sister was shown to have Nephronophthisis Type 3, and a liver biopsy showed early fibrotic changes. Subsequent genetic testing confirmed the index patient as having NPHP Type 3. A kidney biopsy showed focal sclerosed glomeruli with patchy areas of tubular atrophy and related tubulointerstitial changes in keeping with NPHP. We present the first confirmatory case of NPHP from South Africa based on histopathology and genetic testing in a 10-year-old Caucasian female who presented with recurrent attacks of abdominal pain, whose elder sister also presented with CKF and early liver fibrosis, confirmed on biopsy and genetic testing. Conclusion: In low-middle-income countries, genetic testing should be undertaken whenever possible to confirm the diagnosis of NPHP, especially in those with a suggestive biopsy or if there is CKF of unknown aetiology with or without extra-renal manifestations. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
6. Nephronophthisis: a pathological and genetic perspective.
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Wolf, Matthias T. F., Bonsib, Stephen M., Larsen, Christopher P., and Hildebrandt, Friedhelm
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KIDNEY radiography , *AUTOSOMAL recessive polycystic kidney , *KIDNEY failure , *BONES , *VASOPRESSIN , *CILIOPATHY , *CELL physiology , *CENTRAL nervous system , *CELLULAR signal transduction , *DESCRIPTIVE statistics , *GENES , *DNA damage , *RETINA , *LIVER , *JOUBERT syndrome , *DISEASE complications , *ADOLESCENCE , *CHILDREN - Abstract
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most frequent genetic causes for kidney failure (KF) in children and adolescents. Over 20 genes cause NPHP and over 90 genes contribute to renal ciliopathies often involving multiple organs. About 15–20% of NPHP patients have additional extrarenal symptoms affecting other organs than the kidneys. The involvement of additional organ systems in syndromic forms of NPHP is explained by shared expression of most NPHP gene products in centrosomes and primary cilia, a sensory organelle present in most mammalian cells. This finding resulted in the classification of NPHP as a ciliopathy. If extrarenal symptoms are present in addition to NPHP, these disorders are defined as NPHP-related ciliopathies (NPHP-RC) and can involve the retina (e.g., with Senior-Løken syndrome), CNS (central nervous system) (e.g., with Joubert syndrome), liver (e.g., Boichis and Arima syndromes), or bone (e.g., Mainzer-Saldino and Sensenbrenner syndromes). This review focuses on the pathological findings and the recent genetic advances in NPHP and NPHP-RC. Different mechanisms and signaling pathways are involved in NPHP ranging from planar cell polarity, sonic hedgehog signaling (Shh), DNA damage response pathway, Hippo, mTOR, and cAMP signaling. A number of therapeutic interventions appear to be promising, ranging from vasopressin receptor 2 antagonists such as tolvaptan, cyclin-dependent kinase inhibitors such as roscovitine, Hh agonists such as purmorphamine, and mTOR inhibitors such as rapamycin. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Ocular manifestations of renal ciliopathies.
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Salehi, Omar, Mack, Heather, Colville, Deb, Lewis, Debbie, and Savige, Judy
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RISK assessment , *NEPHRITIS , *BIOLOGICAL models , *CILIOPATHY , *RESEARCH funding , *EYE abnormalities , *RETINAL diseases , *TUBEROUS sclerosis , *OCULAR manifestations of general diseases , *CYSTIC kidney disease , *POLYCYSTIC kidney disease , *GENETIC disorders , *COLOBOMA , *PHENOTYPES - Abstract
Renal ciliopathies are a common cause of kidney failure in children and adults, and this study reviewed their ocular associations. Genes affected in renal ciliopathies were identified from the Genomics England Panels. Ocular associations were identified from Medline and OMIM, and the genes additionally examined for expression in the human retina (https://www.proteinatlas.org/humanproteome/tissue) and for an ocular phenotype in mouse models (http://www.informatics.jax.org/). Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma. Diseases associated with pathogenic variants in ANK6, MAPKBP1, NEK8, and TCTN1 have no reported ocular manifestations, as well as low retinal expression and no ocular features in mouse models. Ocular abnormalities are not associated with the most common adult-onset "cystic" kidney diseases, namely, autosomal dominant (AD) polycystic kidney disease and the AD tubulointerstitial kidney diseases (ADTKD). However, other kidney syndromes with cysts have ocular features including papillorenal syndrome (optic disc dysplasia), Hereditary Angiopathy Nephropathy, Aneurysms and muscle Cramps (HANAC) (tortuous retinal vessels), tuberous sclerosis (retinal hamartomas), von Hippel-Lindau syndrome (retinal hemangiomas), and Alport syndrome (lenticonus, fleck retinopathy). Ocular abnormalities are associated with many pediatric-onset renal ciliopathies but are uncommon in adult-onset cystic kidney disease. However the demonstration of ocular manifestations may be helpful diagnostically and the features may require monitoring or treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Human Genetics of Defects of Situs
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Perrot, Andreas, Rickert-Sperling, Silke, Crusio, Wim E., Series Editor, Dong, Haidong, Series Editor, Radeke, Heinfried H., Series Editor, Rezaei, Nima, Series Editor, Steinlein, Ortrud, Series Editor, Xiao, Junjie, Series Editor, Rickert-Sperling, Silke, editor, Kelly, Robert G., editor, and Haas, Nikolaus, editor
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- 2024
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9. Diseases of the primary cilia: a clinical characteristics review
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Alzarka, Bakri, Charnaya, Olga, and Gunay-Aygun, Meral
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- 2024
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10. Immunofluorescence analyses of respiratory epithelial cells aid the diagnosis of nephronophthisis
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Hellmann, Carlotta, Wohlgemuth, Kai, Pennekamp, Petra, George, Sebastian, Dahmer-Heath, Mareike, Konrad, Martin, Omran, Heymut, and König, Jens
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- 2024
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11. Clinical report and genetic analysis of rare premature infant nephronophthisis caused by biallelic TTC21B variants.
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Li, Yingying, Dai, Liying, Xu, Hong, Huang, Jin, Zhang, Jinqiu, Mei, Zhenzhu, and Zhang, Rui
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PREMATURE infants , *CYSTIC kidney disease , *CHRONIC kidney failure , *HEPATIC fibrosis , *LITERATURE reviews , *PATIENT experience - Abstract
Background: Nephronophthisis (NPHP) is a genetically heterogeneous disease that can lead to end‐stage renal disease (ESRD) in children. The TTC21B variant is associated with NPHP12 and mainly characterized by cystic kidney disease, skeletal malformation, liver fibrosis, and retinopathy. Affected patients range from children to adults. Some patients experience ESRD in infancy or early childhood, but clinical reports on neonatal patients are rare. We report a case of NPHP12 in a premature infant and analyze its genetic etiology. Methods: Trio‐whole exome sequencing analysis was performed on the patient and her parents; bioinformatics software was used to predict and analyze the hazards of the variants. Sanger sequencing was performed to verify variants. We calculated the free energy between mutant IFT139 and the IFT121‐IFT122‐IFT43 complex structure using molecular dynamics (MD). Finally, the clinical and genetic characteristics of patients with hotspot variant Cys518Arg were reviewed. Results: Genetic analysis revealed compound‐heterozyous TTC21B variants in the patient, c.497delA (p.Lys166fs*36) and c.1552T>C (p.Cys518Arg). Her father and mother had heterozygous c.497delA (p.Lys166fs*36) and heterozygous c.1552T>C (p.Cys518Arg), respectively. Cys518Arg represents a hotspot variant, and the MD calculation results show that this can reduce the structural stability of the IFT121‐IFT122‐IFT139‐IFT43 complex structure. A literature review showed that Cys518Arg might lead to the early occurrence of ESRD. Conclusions: Compound‐heterozygous TTC21B variants underlie the phenotype in this patient. Thus, Cys518Arg may be a hotspot variant in the Chinese population. Genetic testing should be recommended for NPHP in neonates and early infants. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Diverse retinal-kidney phenotypes associated with NPHP1 homozygous whole-gene deletions in patients with kidney failure.
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Esson, Gavin, Logan, Ian, Wood, Katrina, Browning, Andrew C., and Sayer, John A.
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KIDNEY failure , *PHENOTYPES , *DELETION mutation , *HOMOZYGOSITY , *HEMODIALYSIS - Abstract
A precise diagnosis in medicine allows appropriate disease-specific management. Kidney failure of unknown aetiology remains a frequent diagnostic label within the haemodialysis unit and kidney transplant clinic, accounting for 15–20% of these patients. Approximately 10% of such cases may have an underlying monogenic cause of kidney failure. Modern genetic approaches can provide a precise diagnosis for patients and their families. A search for extra-renal disease manifestations is also important as this may point to a specific genetic diagnosis. Here, we present two patients where molecular genetic testing was performed because of kidney failure of unknown aetiology and associated retinal phenotypes. The first patient reached kidney failure at 16 years of age but only presented with a retinal phenotype at 59 years of age and was found to have evidence of rod-cone dystrophy. The second patient presented with childhood kidney failure at the age of 15 years and developed visual difficulties and photophobia at the age of 32 years and was diagnosed with cone dystrophy. In both cases, genetic tests were performed which revealed a homozygous whole-gene deletion of NPHP1-encoding nephrocystin-1, providing the unifying diagnosis of Senior-Løken syndrome type 1. We conclude that reviewing kidney and extra-renal phenotypes together with targeted genetic testing was informative in these cases of kidney failure of unknown aetiology and associated retinal phenotypes. The involvement of an interdisciplinary team is advisable when managing such patients and allows referral to other relevant specialities. The long time lag and lack of diagnostic clarity and clinical evaluation in our cases should encourage genetic investigations for every young patient with unexplained kidney failure. For these and similar patients, a more timely genetic diagnosis would allow for improved management, a risk assessment of kidney disease in relatives, and the earlier identification of extra-renal disease manifestations. [ABSTRACT FROM AUTHOR]
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- 2024
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13. The Pathophysiology of Inherited Renal Cystic Diseases.
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Satariano, Matthew, Ghose, Shaarav, and Raina, Rupesh
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CYSTIC kidney disease , *AUTOSOMAL recessive polycystic kidney , *POLYCYSTIC kidney disease , *KIDNEY diseases - Abstract
Renal cystic diseases (RCDs) can arise from utero to early adulthood and present with a variety of symptoms including renal, hepatic, and cardiovascular manifestations. It is well known that common RCDs such as autosomal polycystic kidney disease and autosomal recessive kidney disease are linked to genes such as PKD1 and PKHD1, respectively. However, it is important to investigate the genetic pathophysiology of how these gene mutations lead to clinical symptoms and include some of the less-studied RCDs, such as autosomal dominant tubulointerstitial kidney disease, multicystic dysplastic kidney, Zellweger syndrome, calyceal diverticula, and more. We plan to take a thorough look into the genetic involvement and clinical sequalae of a number of RCDs with the goal of helping to guide diagnosis, counseling, and treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Biallelic ANKS6 null variants cause notable extrarenal phenotypes in a nephronophthisis patient and lead to hepatobiliary abnormalities by YAP1 deficiency.
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Liu, Keqiang, Chen, Ru, Wang, Xiaoying, Gong, Yiming, Shi, Jia, Gu, Beilin, Zhou, Ying, and Cai, Wei
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YAP signaling proteins , *RNA splicing , *GENETIC variation , *GENE expression , *PHENOTYPES , *KIDNEY failure - Abstract
The ankyrin repeat and sterile alpha motif domain containing 6 (ANKS6) gene, encoding an inversin compartment protein of the primary cilium, was recently reported as a pathogenic gene of nephronophthisis (MIM PS256100). Extrarenal manifestations are frequently observed in this disease, however, potential genotype–phenotype correlations and the underlying mechanisms remain poorly understood. Here we described an infant with kidney failure, hepatobiliary abnormalities, and heart disease, in whom whole exome sequencing identified compound heterozygous variants in ANKS6, including a novel nonsense variant p.Trp458* and a recurrent splicing variant c.2394+1G > A. mRNA expression studies showed that the splicing variant caused aberrant mRNA splicing with exon 13 skipping and the biallelic variants were predicted to cause loss of ANKS6 function. We systematically characterized the clinical and genetic spectra of the disease and revealed that biallelic null variants in ANKS6 cause more severe kidney disease and more extrarenal manifestations, thus establishing a clear genotype–phenotype correlation for the disease. Further evaluations showed that ANKS6 deficiency reduced YAP1 expression in the patient's bile duct epithelium and ANKS6 promotes YAP1 transcriptional activity in a dose‐dependent manner, indicating that loss of ANKS6 function causes hepatobiliary abnormalities through YAP1 deficiency during biliary morphogenesis and development, which may offer new therapeutic targets. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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15. Scalp Tumor and Hydroureteronephrosis in Patients with Nephronophthisis and Homozygous NPHP1 Deletion.
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Tong, Huajuan, Zhao, Feng, Yang, Yonghui, Qiu, Xiaojian, Zhu, Liying, and Yu, Zihua
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HEAD & neck cancer diagnosis , *CHRONIC kidney failure , *GENETIC mutation , *SEQUENCE analysis , *HYDRONEPHROSIS , *GENETIC testing , *GENETIC polymorphisms , *MEDICAL screening , *CHROMOSOME banding , *KIDNEY diseases , *CELLULAR signal transduction , *RESEARCH funding , *AUTOSOMAL recessive polycystic kidney , *URETER diseases , *PHENOTYPES , *DISEASE complications , *ADOLESCENCE - Abstract
Homozygous deletion of NPHP1 can lead to isolated nephronophthisis (NPHP) and syndromic disorders. However, the phenotype of scalp tumor and hydroureteronephrosis in NPHP patients with homozygous deletion of NPHP1 has not been reported. Clinical data, laboratory results, and genetic testing of 4 NPHP patients were collected. Examination of their eyes, heart, and urinary tract and of their hepatobiliary, skeletal, and central nervous systems was evaluated. Isolated NPHP was observed in 1 case, and syndromic disorders were observed in the other 3 patients. Their syndromic disorders showed NPHP combined with central nervous system defects, eye involvement, scalp tumor, arachnoid cyst, or hydroureteronephrosis. Large homozygous deletions covering the whole NPHP1 gene locus were identified in all 4 patients. We report a novel phenotype of scalp tumor and hydroureteronephrosis in NPHP patients with homozygous deletion of NPHP1, paving an avenue for further research on NPHP1 -associated deformity in the skin and the urinary system. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
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16. Phenotype Spectrum in Tunisian Population with NPHP1 Deletion.
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Hammi, Yousra, Ferjani, Maryem, Meddeb, Rym, Kacem, Rania, Sayari, Taha, Mrad, Ridha, and Gargah, Tahar
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RESEARCH , *CHRONIC kidney failure , *THERAPEUTICS , *GENETIC mutation , *MARRIAGE , *RETROSPECTIVE studies , *ACQUISITION of data , *KIDNEY transplantation , *RENAL replacement therapy , *SURVIVAL rate , *GENOTYPES , *MEDICAL records , *DESCRIPTIVE statistics , *AUTOSOMAL recessive polycystic kidney , *DEMOGRAPHIC characteristics , *STATISTICAL correlation , *CONSANGUINITY , *PHENOTYPES , *SPECTRUM analysis - Abstract
Introduction: Nephronophthisis (NPHP) is a tubulointerstitial kidney disorder with an autosomal recessive inheritance pattern. Its genetic heterogeneity contributes to phenotype variability. The most frequent etiology of juvenile nephronophthisis is a mutation in the nephronophthisis type 1 (NPHP1) gene. This study aimed to evaluate the genotype-phenotype correlation in NPHP1 gene mutation. Methods: A multicenter retrospective study was performed over 20 years from 1998 to 2018 to describe the clinical, biological, and radiological features associated with the large deletion NPHP1 gene in 32 patients. Results: The incidence of NPHP1 was 1.6/204041. Eighty-one percent of our patients were born out of consanguineous marriages. The mean age at diagnosis was 14 ± 7 years. The patients were divided into three groups: isolated nephronophthisis (72%), syndromic nephronophthisis (19%), and patients without recognizable syndrome (9%). Intrafamilial and geographical variability was observed in syndrome diagnoses and in age at the onset of CKD stage 5. Genotype frequency varied between 50% and 100% in genealogical data. Juvenile (47%), adolescent (37%), and adult (13%) clinical forms have been distinguished by the onset of CKD stage 5. The five-year survival rate of renal transplantation was 80%. Conclusion: Given the broad clinical spectrum of NPHP1 associated with the large deletion of the NPHP1 gene, no genotype-phenotype correlation could be established. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
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17. Renal cell carcinoma in an adult-onset ESRD patient with nephronophthisis harboring NPHP3 deletion: A case report
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Zuo-Lin Li, Feng-Mei Wang, Yi Wen, Hai-Feng Ni, Xiao-Liang Zhang, and Bin Wang
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Nephronophthisis ,Renal cysts ,Renal cell carcinoma ,Adult-onset ESRD ,NPHP3 gene ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Background: Nephronophthisis (NPHP) is a rare autosomal recessive inherited tubulointerstitial nephropathy, the most prevalent genetic cause of end-stage renal disease (ESRD) in children. Convincing evidence indicated that the overall prevalence of NPHP in adult-onset ESRD is very likely to be an underestimation. Therefore, understanding the genetic background and clinicopathologic features of adult-onset NPHP is warranted. Case presentation: we reported one intriguing case with concurrent NPHP3 c.2694-2_2694-1delAG (splicing) variant and c.1082C > G (p.S361C) variant. A 48-year-old male was admitted to our hospital, complained about renal dysfunction for 10 years, and found right renal space-occupying lesion for 1 week. One of the most interesting clinical features is adult-onset ESRD, which differs from previous cases. Another discovery of this study is that the NPHP harboring NPHP3 deletion may be associated with clear cell renal cell carcinoma. Conclusion: In conclusion, we report two mutations in the NPHP3 gene that cause NPHP with adult-onset ESRD and renal clear cell carcinoma in a Chinese family, enriching the clinical features of NPHP.
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- 2024
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18. Clinical report and genetic analysis of rare premature infant nephronophthisis caused by biallelic TTC21B variants
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Yingying Li, Liying Dai, Hong Xu, Jin Huang, Jinqiu Zhang, Zhenzhu Mei, and Rui Zhang
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ciliopathy ,end‐stage renal disease ,IFT139 ,nephronophthisis ,TTC21B ,Genetics ,QH426-470 - Abstract
Abstract Background Nephronophthisis (NPHP) is a genetically heterogeneous disease that can lead to end‐stage renal disease (ESRD) in children. The TTC21B variant is associated with NPHP12 and mainly characterized by cystic kidney disease, skeletal malformation, liver fibrosis, and retinopathy. Affected patients range from children to adults. Some patients experience ESRD in infancy or early childhood, but clinical reports on neonatal patients are rare. We report a case of NPHP12 in a premature infant and analyze its genetic etiology. Methods Trio‐whole exome sequencing analysis was performed on the patient and her parents; bioinformatics software was used to predict and analyze the hazards of the variants. Sanger sequencing was performed to verify variants. We calculated the free energy between mutant IFT139 and the IFT121‐IFT122‐IFT43 complex structure using molecular dynamics (MD). Finally, the clinical and genetic characteristics of patients with hotspot variant Cys518Arg were reviewed. Results Genetic analysis revealed compound‐heterozyous TTC21B variants in the patient, c.497delA (p.Lys166fs*36) and c.1552T>C (p.Cys518Arg). Her father and mother had heterozygous c.497delA (p.Lys166fs*36) and heterozygous c.1552T>C (p.Cys518Arg), respectively. Cys518Arg represents a hotspot variant, and the MD calculation results show that this can reduce the structural stability of the IFT121‐IFT122‐IFT139‐IFT43 complex structure. A literature review showed that Cys518Arg might lead to the early occurrence of ESRD. Conclusions Compound‐heterozygous TTC21B variants underlie the phenotype in this patient. Thus, Cys518Arg may be a hotspot variant in the Chinese population. Genetic testing should be recommended for NPHP in neonates and early infants.
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- 2024
- Full Text
- View/download PDF
19. Nephronophthisis and Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)
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König, Jens, Omran, Heymut, Schaefer, Franz, editor, and Greenbaum, Larry A., editor
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- 2023
- Full Text
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20. Ciliopathies: Their Role in Pediatric Kidney Disease
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Schmidts, Miriam, Beales, Philip L., Schaefer, Franz, editor, and Greenbaum, Larry A., editor
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- 2023
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21. Inversin (NPHP2) and Vangl2 are required for normal zebrafish cloaca formation.
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Wang, Hui, Zaiser, Friedemann, Eckert, Priska, Ruf, Johannes, Kayser, Nicolas, Veenstra, Anna C., Müller, Merle, Haas, Rebecca, Walz, Gerd, and Yakulov, Toma A.
- Subjects
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BRACHYDANIO , *CELL polarity , *RECESSIVE genes , *IN situ hybridization , *EPITHELIAL cells , *CILIOPATHY - Abstract
Nephronophthisis (NPH), an autosomal recessive ciliopathy, results from mutations in more than 20 different genes (NPHPs). These gene products form protein complexes that regulate trafficking within the cilium, a microtubular structure that plays a crucial role in developmental processes. Several NPHPs, including NPHP2/Inversin, have been linked to extraciliary functions. In addition to defining a specific segment of primary cilia (Inversin compartment), NPHP2 participates in planar cell polarity (PCP) signaling along with Dishevelled and Vangl family members. We used the mutant zebrafish line invs sa36157, containing a stop codon at amino acid 314, to characterize tissue-specific functions of zebrafish Nphp2. The invs sa36157 line exhibits mild ciliopathy phenotypes and increased glomerular and cloaca cyst formation. These mutants showed enhanced susceptibility to the simultaneous depletion of the nphp1/nphp2/nphp8 module, known to be involved in the cytoskeletal organization of epithelial cells. Notably, simultaneous depletion of zebrafish nphp1 and vangl2 led to a pronounced increase in cloaca malformations in the invs sa36157 mutant embryos. Time-lapse imaging showed that the pronephric cells correctly migrated towards the ectodermal cells in these embryos, but failed to form the cloaca opening. Despite these abnormal developments, cellular fate does not seem to be affected in nphp1 and vangl2 MO-depleted invs sa36157 mutants, as shown by in situ hybridizations for markers of pronephros and ectodermal cell development. However, significantly reduced apoptotic activity was observed in this double knockdown model, signifying the role of apoptosis in cloacal morphogenesis. Our findings underscore the critical interplay of nphp1 , nphp2/Inversin , and vangl2 in orchestrating normal cloaca formation in zebrafish, shedding light on the complex molecular mechanisms underlying ciliopathy-associated phenotypes. • nphp genes depletion causes cysts and cloaca malformation in zebrafish. • invs sa36157 zebrafish exhibit mild ciliopathy phenotypes. • nphp1 and vangl2 depletion worsens cloaca malformation. • nphp1 and vangl2 knockdown impairs cell rearrangement in invs sa36157 mutants. • Cell fate unaffected but altered apoptosis may contribute to cloaca defects. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
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22. 不同基因突变致肾单位肾痨及相关综合征 患儿临床表型特点及基因分析.
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赵雪, 蒋丽君, 戎赞华, 窦志艳, 苏庆晓, 梁钰珩, and 齐兴杰
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GENETIC testing ,SKELETAL dysplasia ,RETINITIS pigmentosa ,KIDNEY physiology ,NUCLEOTIDE sequencing - Abstract
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- 2023
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23. Fluid shear stress triggers cholesterol biosynthesis and uptake in inner medullary collecting duct cells, independently of nephrocystin-1 and nephrocystin-4
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Meriem Garfa Traoré, Federica Roccio, Caterina Miceli, Giulia Ferri, Mélanie Parisot, Nicolas Cagnard, Marie Lhomme, Nicolas Dupont, Alexandre Benmerah, Sophie Saunier, and Marion Delous
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nephronophthisis ,NPHP1 ,NPHP4 ,shear stress ,cholesterol ,Biology (General) ,QH301-705.5 - Abstract
Renal epithelial cells are subjected to fluid shear stress of urine flow. Several cellular structures act as mechanosensors–the primary cilium, microvilli and cell adhesion complexes–that directly relay signals to the cytoskeleton to regulate various processes including cell differentiation and renal cell functions. Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy leading to end-stage kidney failure before adulthood. NPHP1 and NPHP4 are the major genes which code for proteins that form a complex at the transition zone of the primary cilium, a crucial region required for the maintenance of the ciliary composition integrity. These two proteins also interact with signaling components and proteins associated with the actin cytoskeleton at cell junctions. Due to their specific subcellular localization, we wondered whether NPHP1 and NPHP4 could ensure mechanosensory functions. Using a microfluidic set up, we showed that murine inner medullary collecting ductal cells invalidated for Nphp1 or Nphp4 are more responsive to immediate shear exposure with a fast calcium influx, and upon a prolonged shear condition, an inability to properly regulate cilium length and actin cytoskeleton remodeling. Following a transcriptomic study highlighting shear stress-induced gene expression changes, we showed that prolonged shear triggers both cholesterol biosynthesis pathway and uptake, processes that do not seem to involve neither NPHP1 nor NPHP4. To conclude, our study allowed us to determine a moderate role of NPHP1 and NPHP4 in flow sensation, and to highlight a new signaling pathway induced by shear stress, the cholesterol biosynthesis and uptake pathways, which would allow cells to cope with mechanical stress by strengthening their plasma membrane through the supply of cholesterol.
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- 2023
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24. Cystic kidney diseases in children.
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De Groof, J., Dachy, A., Breysem, L., and Mekahli, D.
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CYSTIC kidney disease , *CHILDREN'S health , *AGE of onset , *DISEASE progression , *TUBEROUS sclerosis - Abstract
Cystic kidney disease comprises a broad group of heterogeneous diseases, which differ greatly in age at onset, disease manifestation, systemic involvement, disease progression, and long-term prognosis. As our understanding of these diseases continues to evolve and new treatment strategies continue to emerge, correctly differentiating and diagnosing these diseases becomes increasingly important. In this review, we aim to highlight the key features of the most relevant cystic kidney diseases, underscore important diagnostic characteristics of each disease, and present specific management options if applicable. [ABSTRACT FROM AUTHOR]
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- 2023
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25. Genotype and phenotype analysis and transplantation strategy in children with kidney failure caused by NPHP.
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Li, Jianyi, Su, Xiaojun, Zhang, Huanxi, Wu, Wenrui, Li, Jianming, Chen, Yanxu, Li, Jun, Fu, Qian, Wu, Chenglin, Zhong, Xuhui, Wang, Changxi, and Liu, Longshan
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SEQUENCE analysis , *GENETIC mutation , *CHOLESTASIS , *KIDNEY failure , *KIDNEY transplantation , *RETROSPECTIVE studies , *CIRRHOSIS of the liver , *GENOTYPES , *BILE acids , *RESEARCH funding , *CYSTIC kidney disease , *PHENOTYPES - Abstract
Background: Nephronophthisis-related ciliopathies (NPHP-RC) have strong genotype and phenotype heterogeneity, and the transplantation strategy of Boichis syndrome is still controversial. Our purpose was to examine associations of genotype and phenotype in children with NPHP-RC and analyze the transplantation strategies of different phenotypes. Methods: The records of children with NPHP treated at our center from 01/2018 to 03/2021 were retrospectively reviewed. Inclusion criteria were a diagnosis of NPHP, received kidney transplantation, and received whole exome sequencing (WES) or nephropathy gene panel testing. Results: Twenty-nine children with NPHP were included. Nine children (31%) had NPHP1 mutations, and all presented with isolated nephropathy. Eighteen of 20 patients with non-NPHP1 mutations had compound heterozygous mutations, and 70% had extrarenal phenotype. Age at disease presentation (11.2 ± 1.94 years) and the development of kidney failure (12.4 ± 2.70 years) were later in children with NPHP1 mutations than those with non-NPHP1 mutations (5.2 ± 2.83 years and 5.7 ± 2.92 years, respectively). Four of six children with NPHP3 mutations were diagnosed with Boichis syndrome due to liver fibrosis. Isolated kidney transplantation resulted in good outcomes for patients with mild or moderate liver fibrosis without portal hypertension, while cholestasis was common postoperatively and could be resolved with ursodeoxycholic acid. Conclusions: NPHP1 mutations are the most common in children with NPHP, and the phenotype of NPHP1 mutation is significantly different from that of non-NPHP1 mutation. For NPHP patients with mild to moderate liver fibrosis without portal hypertension, timely treatment of cholestasis could prevent the rapid progression of liver function damage after isolated kidney transplantation. [ABSTRACT FROM AUTHOR]
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- 2023
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26. Nephronophthisis and Related Ciliopathies
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Braun, Daniela A., Hildebrandt, Friedhelm, Emma, Francesco, editor, Goldstein, Stuart L., editor, Bagga, Arvind, editor, Bates, Carlton M., editor, and Shroff, Rukshana, editor
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- 2022
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27. Other Cystic Kidney Diseases
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Rumjon, Adam and Harber, Mark, editor
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- 2022
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28. Genetic Tubulointerstitial Disease and Nephronophthisis
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Gage, Alice, Illeperuma, Buddhika, Harber, Mark, and Harber, Mark, editor
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- 2022
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29. Genetic Diseases Associated with Tubulointerstitial Nephritis
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Wolf, Matthias T. F., Besse, Whitney, Bleyer, Anthony J., Dahl, Neera K., Atta, Mohamed G., editor, and Perazella, Mark A., editor
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- 2022
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30. Congenital Hepatic Fibrosis, Caroli’s Disease, and Other Fibrocystic Liver Diseases
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Rock, N. M., Kanavaki, I., McLin, V. A., Guandalini, Stefano, editor, and Dhawan, Anil, editor
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- 2022
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31. Biallelic mutations of TTC12 and TTC21B were identified in Chinese patients with multisystem ciliopathy syndromes
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Weicheng Chen, Feifei Wang, Weijia Zeng, Xinyan Zhang, Libing Shen, Yuan Zhang, and Xiangyu Zhou
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Situs inversus ,Heterotaxy ,Congenital heart disease ,Nephronophthisis ,Neonatal cholestasis ,Ciliopathy ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Abnormalities in cilia ultrastructure and function lead to a range of human phenotypes termed ciliopathies. Many tetratricopeptide repeat domain (TTC) family members have been reported to play critical roles in cilium organization and function. Results Here, we describe five unrelated family trios with multisystem ciliopathy syndromes, including situs abnormality, complex congenital heart disease, nephronophthisis or neonatal cholestasis. Through whole-exome sequencing and Sanger sequencing confirmation, we identified compound heterozygous mutations of TTC12 and TTC21B in six affected individuals of Chinese origin. These nonsynonymous mutations affected highly conserved residues and were consistently predicted to be pathogenic. Furthermore, ex vivo cDNA amplification demonstrated that homozygous c.1464 + 2 T > C of TTC12 would cause a whole exon 16 skipping. Both mRNA and protein levels of TTC12 were significantly downregulated in the cells derived from the patient carrying TTC12 mutation c.1464 + 2 T > C by real-time qPCR and immunofluorescence assays when compared with two healthy controls. Transmission electron microscopy analysis further identified ultrastructural defects of the inner dynein arms in this patient. Finally, the effect of TTC12 deficiency on cardiac LR patterning was recapitulated by employing a morpholino-mediated knockdown of ttc12 in zebrafish. Conclusions To the best of our knowledge, this is the first study reporting the association between TTC12 variants and ciliopathies in a Chinese population. In addition to nephronophthisis and laterality defects, our findings demonstrated that TTC21B should also be considered a candidate gene for biliary ciliopathy, such as TTC26, which further expands the phenotypic spectrum of TTC21B deficiency in humans.
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- 2022
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32. Cystic Diseases of the Kidneys: From Bench to Bedside.
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Raina, Rupesh, Lomanta, Francis, Singh, Siddhartha, Anand, Alisha, Kalra, Riti, Enukonda, Vignasiddh, Barat, Oren, Pandher, Davinder, and Sethi, Sidharth K.
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NEUROCUTANEOUS disorders , *POLYCYSTIC kidney disease , *LAURENCE-Moon-Biedl syndrome , *INTERSTITIAL nephritis , *VON Hippel-Lindau disease , *ZELLWEGER Syndrome , *GENETIC testing , *CELLULAR signal transduction , *CELLS , *CYSTIC kidney disease , *GENETIC counseling , *AUTOSOMAL recessive polycystic kidney , *JOUBERT syndrome , *TUBEROUS sclerosis - Abstract
Exploration into the causes of hereditary renal cystic diseases demonstrates a deep-rooted connection with the proteomic components of the cellular organelle cilia. Cilia are essential to the signaling cascades, and their dysfunction has been tied to a range of renal cystic diseases initiating with studies on the oak ridge polycystic kidney (ORPK) mouse model. Here, we delve into renal cystic pathologies that have been tied with ciliary proteosome and highlight the genetics associated with each. The pathologies are grouped based on the mode of inheritance, where inherited causes that result in cystic kidney disease phenotypes include autosomal dominant and autosomal recessive polycystic kidney disease, nephronophthisis (Bardet--Biedl syndrome and Joubert Syndrome), and autosomal dominant tubulointerstitial kidney disease. Alternatively, phakomatoses-, also known as neurocutaneous syndromes, associated cystic kidney diseases include tuberous sclerosis (TS) and Von Hippel--Lindau (VHL) disease. Additionally, we group the pathologies by the mode of inheritance to discuss variations in recommendations for genetic testing for biological relatives of a diagnosed individual. [ABSTRACT FROM AUTHOR]
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- 2023
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33. Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis.
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Hu, Qiulei, Lai, Jiayong, Chen, Huamu, Cai, Yong, Yue, Zhihui, Lin, Hongrong, and Sun, Liangzhong
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CYSTIC kidney disease , *GUANINE nucleotide exchange factors , *GUANOSINE triphosphate , *CHRONIC kidney failure - Abstract
Nephronophthisis (NPHP) is the most prevalent monogenic disease leading to end-stage renal failure in childhood. RhoA activation is involved in NPHP pathogenesis. This study explored the role of the RhoA activator guanine nucleotide exchange factor (GEF)-H1 in NPHP pathogenesis. We analyzed the expression and distribution of GEF-H1 in NPHP1 knockout (NPHP1KO) mice using Western blotting and immunofluorescence, followed by GEF-H1 knockdown. Immunofluorescence and renal histology were used to examine the cysts, inflammation, and fibrosis. A RhoA GTPase activation assay and Western blotting were used to detect the expression of downstream GTP-RhoA and p-MLC2, respectively. In NPHP1 knockdown (NPHP1KD) human kidney proximal tubular cells (HK2 cells), we detected the expressions of E-cadherin and α-smooth muscle actin (α-SMA). In vivo, increased expression and redistribution of GEF-H1, and higher levels of GTP-RhoA and p-MLC2 in renal tissue of NPHP1KO mice were observed, together with renal cysts, fibrosis, and inflammation. These changes were alleviated by GEF-H1 knockdown. In vitro, the expression of GEF-H1 and activation of RhoA were also increased, with increased expression of α-SMA and decreased E-cadherin. GEF-H1 knockdown reversed these changes in NPHP1KD HK2 cells. Thus, the GEF-H1/RhoA/MLC2 axis is activated in NPHP1 defects and may play a pivotal role in NPHP pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2023
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34. A 5-year-old girl with kidney impairment and severe anemia: Answers.
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Steinman, Benjamin, Del Rio, Marcela, Zolotnitskaya, Anna, and Hayde, Nicole
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GENETIC mutation , *SEQUENCE analysis , *DIFFERENTIAL diagnosis , *GENETIC testing , *MAGNETIC resonance imaging , *SEVERITY of illness index , *ANEMIA , *CILIOPATHY , *AUTOSOMAL recessive polycystic kidney , *URINALYSIS , *ACUTE kidney failure , *CHILDREN - Abstract
A quiz concerning 5‑year‑old girl with kidney impairment and severe anemia.
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- 2023
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35. Identification of renal cyst cells of type I Nephronophthisis by single-nucleus RNA sequencing
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Qianying Wang, Baojuan Zou, Xiaoya Wei, Hongrong Lin, Changmiao Pang, Lei Wang, Jinglin Zhong, Huamu Chen, Xuefei Gao, Min Li, Albert C. M. Ong, Zhihui Yue, and Liangzhong Sun
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renal cyst ,single-nucleus RNA sequencing ,Nephronophthisis ,NPHP1 ,Niban1 ,Biology (General) ,QH301-705.5 - Abstract
Background: Nephronophthisis (NPH) is the most common genetic cause of end-stage renal disease (ESRD) in childhood, and NPHP1 is the major pathogenic gene. Cyst formation at the corticomedullary junction is a pathological feature of NPH, but the mechanism underlying cystogenesis is not well understood. The isolation and identification of cystic cell subpopulation could help to identify their origins and provide vital clues to the mechanisms underlying cystogenesis in NPH.Methods: Single-nucleus RNA sequencing (snRNA-seq) was performed to produce an atlas of NPHP1 renal cells. Kidney samples were collected from WT (Nphp1+/+) mice and NPHP1 (Nphp1del2-20/del2-20) model mice.Results: A comprehensive atlas of the renal cellular landscape in NPHP1 was generated, consisting of 14 basic renal cell types as well as a subpopulation of DCT cells that was overrepresented in NPHP1 kidneys compared to WT kidneys. GO analysis revealed significant downregulation of genes associated with tubular development and kidney morphogenesis in this subpopulation. Furthermore, the reconstruction of differentiation trajectories of individual cells within this subpopulation confirmed that a specific group of cells in NPHP1 mice become arrested at an early stage of differentiation and proliferate to form cysts. We demonstrate that Niban1 is a specific molecular marker of cystic cells in both mice and human NPHP1.Conclusion: In summary, we report a novel subpopulation of DCT cells, marked by Niban1, that are classified as cystic cells in the NPHP1 mice kidney. These results offer fresh insights into the cellular and molecular basis of cystogenesis in NPH.
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- 2023
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36. A single heterozygous nonsense mutation in the TTC21B gene causes adult‐onset nephronophthisis 12: A case report and review of literature.
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Wang, Dan, Chen, Xionghui, Wen, Qiong, Li, Zhijian, Chen, Wei, Chen, Wenfang, and Wang, Xin
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NONSENSE mutation , *CYSTIC kidney disease , *GENETIC mutation , *GENETIC disorders , *LITERATURE reviews , *FAMILIAL spastic paraplegia - Abstract
Background: Nephronophthisis type 12 (NPHP 12) is a rare cilia‐related cystic kidney disease, caused by TTC21B mutation, mainly involving the kidneys, which generally occurs in children. Our study aimed to illustrate its clinical, pathological and genetic characteristics by reporting an adult‐onset case of NPHP 12 caused by a single heterozygous nonsense mutation of TTC21B confirmed by renal histology and whole exome sequencing and reviewing related literature with a comparative analysis of the clinical features of each case. It will further increase the recognition of this rare kidney genetic disease, which sometimes can manifest as an adult disease. Results: A 33‐years‐old man showed a chronic disease course, and he exhibited slight renal dysfunction (CKD stage 3, eGFR = 49 ml/[min* 1.73 m2]) with renal tubular proteinuria, without any extrarenal manifestations, congenital malformation history of kidney disease, or family hereditary disease. Renal histological findings showed substantial interstitial fibrosis with some irregular and tortuous tubules with complex branches and segmental thickening and splitting of the tubular basement membrane. The patient was diagnosed with chronic interstitial nephritis for an unknown reason clinically. Further genetic analysis revealed a single heterozygous nonsense mutation in the TTC21B gene and NPHP 12 was diagnosed finally. Conclusion: A single heterozygous mutation in the TTC21B gene may cause atypical NPHP12, which had a relatively later onset and milder clinical symptoms without developmental abnormalities. Therefore, for unexplained adult‐onset chronic interstitial nephritis with unusual changes of renal tubules and interstitial fibrosis, even without a clear history of hereditary kidney disease, genetic testing is still recommended. The correct diagnosis of this rare adult‐onset hereditary nephropathy can avoid unnecessary treatment. [ABSTRACT FROM AUTHOR]
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- 2022
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37. Immunofluorescence analyses of respiratory epithelial cells aid the diagnosis of nephronophthisis.
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MISSENSE mutation , *GENETIC disorder diagnosis , *EPITHELIAL cells , *WESTERN immunoblotting , *KIDNEY failure - Abstract
Background: Nephronophthisis (NPH) comprises a heterogeneous group of inherited renal ciliopathies clinically characterized by progressive kidney failure. So far, definite diagnosis is based on molecular testing only. Here, we studied the feasibility of NPHP1 and NPHP4 immunostaining of nasal epithelial cells to secure and accelerate the diagnosis of NPH.Samples of 86 individuals with genetically determined renal ciliopathies were analyzed for NPHP1 localization using immunofluorescence microscopy (IF). A sub-cohort of 35 individuals was also analyzed for NPHP4 localization. Western blotting was performed to confirm IF results.NPHP1 and NPHP4 were both absent in all individuals with disease-causing
NPHP1 variants including one with a homozygous missense variant (c.1027G > A; p.Gly343Arg) formerly classified as a “variant of unknown significance.” In individuals with anNPHP4 genotype, we observed a complete absence of NPHP4 while NPHP1 was severely reduced. IF results were confirmed by immunoblotting. Variants in other genes related to renal ciliopathies did not show any impact on NPHP1/NPHP4 expression. Aberrant immunostaining in two genetically unsolved individuals gave rise for a further genetic workup resulting in a genetic diagnosis for both with disease-causing variants inNPHP1 andNPHP4 , respectively.IF of patient-derived respiratory epithelial cells may help to secure and accelerate the diagnosis of nephronophthisis—both by verifying inconclusive genetic results and by stratifying genetic diagnostic approaches. Furthermore, we provide in vivo evidence for the interaction of NPHP1 and NPHP4 in a functional module.A higher-resolution version of the Graphical abstract is available as Supplementary informationA higher-resolution version of the Graphical abstract is available as Supplementary informationMethods: Nephronophthisis (NPH) comprises a heterogeneous group of inherited renal ciliopathies clinically characterized by progressive kidney failure. So far, definite diagnosis is based on molecular testing only. Here, we studied the feasibility of NPHP1 and NPHP4 immunostaining of nasal epithelial cells to secure and accelerate the diagnosis of NPH.Samples of 86 individuals with genetically determined renal ciliopathies were analyzed for NPHP1 localization using immunofluorescence microscopy (IF). A sub-cohort of 35 individuals was also analyzed for NPHP4 localization. Western blotting was performed to confirm IF results.NPHP1 and NPHP4 were both absent in all individuals with disease-causingNPHP1 variants including one with a homozygous missense variant (c.1027G > A; p.Gly343Arg) formerly classified as a “variant of unknown significance.” In individuals with anNPHP4 genotype, we observed a complete absence of NPHP4 while NPHP1 was severely reduced. IF results were confirmed by immunoblotting. Variants in other genes related to renal ciliopathies did not show any impact on NPHP1/NPHP4 expression. Aberrant immunostaining in two genetically unsolved individuals gave rise for a further genetic workup resulting in a genetic diagnosis for both with disease-causing variants inNPHP1 andNPHP4 , respectively.IF of patient-derived respiratory epithelial cells may help to secure and accelerate the diagnosis of nephronophthisis—both by verifying inconclusive genetic results and by stratifying genetic diagnostic approaches. Furthermore, we provide in vivo evidence for the interaction of NPHP1 and NPHP4 in a functional module.A higher-resolution version of the Graphical abstract is available as Supplementary informationA higher-resolution version of the Graphical abstract is available as Supplementary informationResults: Nephronophthisis (NPH) comprises a heterogeneous group of inherited renal ciliopathies clinically characterized by progressive kidney failure. So far, definite diagnosis is based on molecular testing only. Here, we studied the feasibility of NPHP1 and NPHP4 immunostaining of nasal epithelial cells to secure and accelerate the diagnosis of NPH.Samples of 86 individuals with genetically determined renal ciliopathies were analyzed for NPHP1 localization using immunofluorescence microscopy (IF). A sub-cohort of 35 individuals was also analyzed for NPHP4 localization. Western blotting was performed to confirm IF results.NPHP1 and NPHP4 were both absent in all individuals with disease-causingNPHP1 variants including one with a homozygous missense variant (c.1027G > A; p.Gly343Arg) formerly classified as a “variant of unknown significance.” In individuals with anNPHP4 genotype, we observed a complete absence of NPHP4 while NPHP1 was severely reduced. IF results were confirmed by immunoblotting. Variants in other genes related to renal ciliopathies did not show any impact on NPHP1/NPHP4 expression. Aberrant immunostaining in two genetically unsolved individuals gave rise for a further genetic workup resulting in a genetic diagnosis for both with disease-causing variants inNPHP1 andNPHP4 , respectively.IF of patient-derived respiratory epithelial cells may help to secure and accelerate the diagnosis of nephronophthisis—both by verifying inconclusive genetic results and by stratifying genetic diagnostic approaches. Furthermore, we provide in vivo evidence for the interaction of NPHP1 and NPHP4 in a functional module.A higher-resolution version of the Graphical abstract is available as Supplementary informationA higher-resolution version of the Graphical abstract is available as Supplementary informationConclusions: Nephronophthisis (NPH) comprises a heterogeneous group of inherited renal ciliopathies clinically characterized by progressive kidney failure. So far, definite diagnosis is based on molecular testing only. Here, we studied the feasibility of NPHP1 and NPHP4 immunostaining of nasal epithelial cells to secure and accelerate the diagnosis of NPH.Samples of 86 individuals with genetically determined renal ciliopathies were analyzed for NPHP1 localization using immunofluorescence microscopy (IF). A sub-cohort of 35 individuals was also analyzed for NPHP4 localization. Western blotting was performed to confirm IF results.NPHP1 and NPHP4 were both absent in all individuals with disease-causingNPHP1 variants including one with a homozygous missense variant (c.1027G > A; p.Gly343Arg) formerly classified as a “variant of unknown significance.” In individuals with anNPHP4 genotype, we observed a complete absence of NPHP4 while NPHP1 was severely reduced. IF results were confirmed by immunoblotting. Variants in other genes related to renal ciliopathies did not show any impact on NPHP1/NPHP4 expression. Aberrant immunostaining in two genetically unsolved individuals gave rise for a further genetic workup resulting in a genetic diagnosis for both with disease-causing variants inNPHP1 andNPHP4 , respectively.IF of patient-derived respiratory epithelial cells may help to secure and accelerate the diagnosis of nephronophthisis—both by verifying inconclusive genetic results and by stratifying genetic diagnostic approaches. Furthermore, we provide in vivo evidence for the interaction of NPHP1 and NPHP4 in a functional module.A higher-resolution version of the Graphical abstract is available as Supplementary informationA higher-resolution version of the Graphical abstract is available as Supplementary informationGraphical abstract: Nephronophthisis (NPH) comprises a heterogeneous group of inherited renal ciliopathies clinically characterized by progressive kidney failure. So far, definite diagnosis is based on molecular testing only. Here, we studied the feasibility of NPHP1 and NPHP4 immunostaining of nasal epithelial cells to secure and accelerate the diagnosis of NPH.Samples of 86 individuals with genetically determined renal ciliopathies were analyzed for NPHP1 localization using immunofluorescence microscopy (IF). A sub-cohort of 35 individuals was also analyzed for NPHP4 localization. Western blotting was performed to confirm IF results.NPHP1 and NPHP4 were both absent in all individuals with disease-causingNPHP1 variants including one with a homozygous missense variant (c.1027G > A; p.Gly343Arg) formerly classified as a “variant of unknown significance.” In individuals with anNPHP4 genotype, we observed a complete absence of NPHP4 while NPHP1 was severely reduced. IF results were confirmed by immunoblotting. Variants in other genes related to renal ciliopathies did not show any impact on NPHP1/NPHP4 expression. Aberrant immunostaining in two genetically unsolved individuals gave rise for a further genetic workup resulting in a genetic diagnosis for both with disease-causing variants inNPHP1 andNPHP4 , respectively.IF of patient-derived respiratory epithelial cells may help to secure and accelerate the diagnosis of nephronophthisis—both by verifying inconclusive genetic results and by stratifying genetic diagnostic approaches. Furthermore, we provide in vivo evidence for the interaction of NPHP1 and NPHP4 in a functional module.A higher-resolution version of the Graphical abstract is available as Supplementary informationA higher-resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
38. Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants
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Jun Wang, Holly R. Thomas, Robert G. Thompson, Stephanie C. Waldrep, Joseph Fogerty, Ping Song, Zhang Li, Yongjie Ma, Peu Santra, Jonathan D. Hoover, Nan Cher Yeo, Iain A. Drummond, Bradley K. Yoder, Jeffrey D. Amack, Brian Perkins, and John M. Parant
- Subjects
cilia ,transition zone ,meckel syndrome ,nephronophthisis ,joubert syndrome ,zebrafish ,penetrance ,pronephric cysts ,retinal degeneration ,scoliosis ,crispr ,crispant ,Medicine ,Pathology ,RB1-214 - Published
- 2022
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39. A single heterozygous nonsense mutation in the TTC21B gene causes adult‐onset nephronophthisis 12: A case report and review of literature
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Dan Wang, Xionghui Chen, Qiong Wen, Zhijian Li, Wei Chen, Wenfang Chen, and Xin Wang
- Subjects
chronic kidney disease ,ciliopathy ,nephronophthisis ,TTC21B ,Genetics ,QH426-470 - Abstract
Abstract Background Nephronophthisis type 12 (NPHP 12) is a rare cilia‐related cystic kidney disease, caused by TTC21B mutation, mainly involving the kidneys, which generally occurs in children. Our study aimed to illustrate its clinical, pathological and genetic characteristics by reporting an adult‐onset case of NPHP 12 caused by a single heterozygous nonsense mutation of TTC21B confirmed by renal histology and whole exome sequencing and reviewing related literature with a comparative analysis of the clinical features of each case. It will further increase the recognition of this rare kidney genetic disease, which sometimes can manifest as an adult disease. Results A 33‐years‐old man showed a chronic disease course, and he exhibited slight renal dysfunction (CKD stage 3, eGFR = 49 ml/[min* 1.73 m2]) with renal tubular proteinuria, without any extrarenal manifestations, congenital malformation history of kidney disease, or family hereditary disease. Renal histological findings showed substantial interstitial fibrosis with some irregular and tortuous tubules with complex branches and segmental thickening and splitting of the tubular basement membrane. The patient was diagnosed with chronic interstitial nephritis for an unknown reason clinically. Further genetic analysis revealed a single heterozygous nonsense mutation in the TTC21B gene and NPHP 12 was diagnosed finally. Conclusion A single heterozygous mutation in the TTC21B gene may cause atypical NPHP12, which had a relatively later onset and milder clinical symptoms without developmental abnormalities. Therefore, for unexplained adult‐onset chronic interstitial nephritis with unusual changes of renal tubules and interstitial fibrosis, even without a clear history of hereditary kidney disease, genetic testing is still recommended. The correct diagnosis of this rare adult‐onset hereditary nephropathy can avoid unnecessary treatment.
- Published
- 2022
- Full Text
- View/download PDF
40. Biallelic mutations of TTC12 and TTC21B were identified in Chinese patients with multisystem ciliopathy syndromes.
- Author
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Chen, Weicheng, Wang, Feifei, Zeng, Weijia, Zhang, Xinyan, Shen, Libing, Zhang, Yuan, and Zhou, Xiangyu
- Abstract
Background: Abnormalities in cilia ultrastructure and function lead to a range of human phenotypes termed ciliopathies. Many tetratricopeptide repeat domain (TTC) family members have been reported to play critical roles in cilium organization and function. Results: Here, we describe five unrelated family trios with multisystem ciliopathy syndromes, including situs abnormality, complex congenital heart disease, nephronophthisis or neonatal cholestasis. Through whole-exome sequencing and Sanger sequencing confirmation, we identified compound heterozygous mutations of TTC12 and TTC21B in six affected individuals of Chinese origin. These nonsynonymous mutations affected highly conserved residues and were consistently predicted to be pathogenic. Furthermore, ex vivo cDNA amplification demonstrated that homozygous c.1464 + 2 T > C of TTC12 would cause a whole exon 16 skipping. Both mRNA and protein levels of TTC12 were significantly downregulated in the cells derived from the patient carrying TTC12 mutation c.1464 + 2 T > C by real-time qPCR and immunofluorescence assays when compared with two healthy controls. Transmission electron microscopy analysis further identified ultrastructural defects of the inner dynein arms in this patient. Finally, the effect of TTC12 deficiency on cardiac LR patterning was recapitulated by employing a morpholino-mediated knockdown of ttc12 in zebrafish. Conclusions: To the best of our knowledge, this is the first study reporting the association between TTC12 variants and ciliopathies in a Chinese population. In addition to nephronophthisis and laterality defects, our findings demonstrated that TTC21B should also be considered a candidate gene for biliary ciliopathy, such as TTC26, which further expands the phenotypic spectrum of TTC21B deficiency in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
41. The Joubert–Meckel–Nephronophthisis Spectrum of Ciliopathies.
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Van De Weghe, Julie C., Gomez, Arianna, and Doherty, Dan
- Abstract
The Joubert syndrome (JS), Meckel syndrome (MKS), and nephronophthisis (NPH) ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human genetics over the past half century. Progress in understanding these conditions illustrates many core concepts of human genetics. The JS phenotype alone is caused by pathogenic variants in more than 40 genes; remarkably, all of the associated proteins function in and around the primary cilium. Primary cilia are near-ubiquitous, microtubule-based organelles that play crucial roles in development and homeostasis. Protruding from the cell, these cellular antennae sense diverse signals and mediate Hedgehog and other critical signaling pathways. Ciliary dysfunction causes many human conditions termed ciliopathies, which range from multiple congenital malformations to adult-onset single-organ failure. Research on the genetics of the JS-MKS-NPH spectrum has spurred extensive functional work exploring the broadly important role of primary cilia in health and disease. This functional work promises to illuminate the mechanisms underlying JS-MKS-NPH in humans, identify therapeutic targets across genetic causes, and generate future precision treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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42. Bilateral Perisylvian Polymicrogyria, Intellectual Disability and Nephronophthisis Associated With Compound Heterozygous Pathogenic Variants in the CEP83 Gene.
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Parrini E, Balestrini S, Rutigliano D, Ricci ML, Mei D, and Guerrini R
- Abstract
The centrosomal protein 83 (CEP83) is a centriolar protein involved in primary cilium assembly, an early and critical step in ciliogenesis. Bi-allelic pathogenic variants in the CEP83 gene have been associated with infantile nephronophthisis and, in a few patients, retinitis pigmentosa. We describe a 5-year-old boy with bilateral perisylvian polymicrogyria, intellectual disability, and nephronophthisis in whom, using exome sequencing, we identified the c.1052T>G p.(Leu351*) stopgain variant inherited from the father and the c.2024T>C p.(Leu675Pro) missense variant inherited from the mother, in a compound heterozygous pattern. Polymicrogyria or, in general, malformations of cortical development had not been previously observed in patients with pathogenic CEP83 variants. However, defects in CEP83 can affect the formation and function of cilia or centrosomal structures, resulting in a polymicrogyric pattern overlapping with that associated with pathogenic variants affecting other genes coding for centrosomal components. This observation expands the spectrum of phenotypes associated with the CEP83 gene and adds it to the list of genes associated with bilateral perisylvian polymicrogyria., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2024
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43. Renal Pathology of Ciliopathies.
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Sekar T and Sebire NJ
- Subjects
- Humans, Kidney pathology, Cilia pathology, Cilia metabolism, Kidney Diseases pathology, Kidney Diseases genetics, Ciliopathies genetics, Ciliopathies pathology, Ciliopathies diagnosis
- Abstract
Renal ciliopathies are a group of genetic disorders that affect the function of the primary cilium in the kidney, as well as other organs. Since primary cilia are important for regulation of cell signaling pathways, ciliary dysfunction results in a range of clinical manifestations, including renal failure, cyst formation, and hypertension. We summarize the current understanding of the pathophysiological and pathological features of renal ciliopathies in childhood, including autosomal dominant and recessive polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome, as well as skeletal dysplasia associated renal ciliopathies. The genetic basis of these disorders is now well-established in many cases, with mutations in a large number of cilia-related genes such as PKD1 , PKD2 , BBS , MKS , and NPHP being responsible for the majority of cases. Renal ciliopathies are broadly characterized by development of interstitial fibrosis and formation of multiple renal cysts which gradually enlarge and replace normal renal tissue, with each condition demonstrating subtle differences in the degree, location, and age-related development of cysts and fibrosis. Presentation varies from prenatal diagnosis of congenital multisystem syndromes to an asymptomatic childhood with development of complications in later adulthood and therefore clinicopathological correlation is important, including increasing use of targeted genetic testing or whole genome sequencing, allowing greater understanding of genetic pathophysiological mechanisms., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2024
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44. Agonists of prostaglandin E2 receptors as potential first in class treatment for nephronophthisis and related ciliopathies.
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Garcia, Hugo, Serafin, Alice S., Silbermann, Flora, Porée, Esther, Viau, Amandine, Mahaut, Clémentine, Billot, Katy, Birgy, Éléonore, Garfa-Traore, Meriem, Roy, Stéphanie, Ceccarelli, Salomé, Mehraz, Manon, Rodriguez, Pamela C., Deleglise, Bérangère, Furio, Laetitia, Jabot-Hanin, Fabienne, Cagnard, Nicolas, Nery, Elaine Del, Fila, Marc, and Sin-Monnot, Soraya
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- *
PROSTAGLANDIN receptors , *CHRONIC kidney failure , *EXTRACELLULAR matrix , *CYTOSKELETON , *CELL cycle , *HEMODIALYSIS patients - Abstract
Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using a medium-throughput drug-screen in NPHP1 knockdown cells, we identified 51 Food and Drug Administration-approved compounds by their ability to alleviate the cellular phenotypes associated with the loss of NPHP1; 11 compounds were further selected for their physicochemical properties. Among those compounds, prostaglandin E1 (PGE1) rescued ciliogenesis defects in immortalized patient NPHP1 urine-derived renal tubular cells, and improved ciliary and kidney phenotypes in our NPH zebrafish and Nphp1 knockout mouse models. Furthermore, Taprenepag, a nonprostanoid prostaglandin E2 receptor agonist, alleviated the severe retinopathy observed in Nphp1−/− mice. Finally, comparative transcriptomics allowed identification of key signaling pathways downstream PGE1, including cell cycle progression, extracellular matrix, adhesion, or actin cytoskeleton organization. In conclusion, using in vitro and in vivo models, we showed that prostaglandin E2 receptor agonists can ameliorate several of the pleotropic phenotypes caused by the absence of NPHP1; this opens their potential as a first therapeutic option for juvenile NPH-associated ciliopathies. [ABSTRACT FROM AUTHOR]
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- 2022
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45. Atypical histological abnormalities in an adult patient with nephronophthisis harboring NPHP1 deletion: a case report
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Maiko Akira, Hitoshi Suzuki, Arisa Ikeda, Masako Iwasaki, Daisuke Honda, Hisatsugu Takahara, Hisaki Rinno, Shigeki Tomita, and Yusuke Suzuki
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Nephronophthisis ,Distal tubule ,Renal biopsy ,End-stage renal failure ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background Nephronophthisis (NPHP) is a chronic tubular interstitial disorder that exhibits an autosomal recessive genetic form and causes progressive renal failure in children. Patients with NPHP rarely show urinary abnormalities, edema, or hypertension. Thus, NPHP is often detected only when renal failure becomes advanced. NPHP can be divided into three types based on the age of end-stage renal failure, i.e., infant type (approximately 5 years old), juvenile type (approximately 13–14 years old), and adolescent type (approximately 19 years old). Here, we report a case of NPHP diagnosed by genetic analysis at 26 years of age with atypical histological abnormalities. Case presentation A 26-year-old woman showed no growth disorders or urinary abnormalities in annual school physical examinations. However, at a check-up at 26 years old, she exhibited renal dysfunction (eGFR 26 mL/min/1.73 m2). Urine tests indicated low specific gravity of urine, but not proteinuria or microscopic hematuria. Urinary β2-microglobulin was high (805 μg/L), and renal biopsy was performed for definitive diagnosis. Histological findings showed no significant findings in glomeruli. However, moderate fibrosis was observed in the interstitial area, and moderate atrophy was observed in the tubules. There were no significant findings in immunofluorescence analysis, and no electron dense deposits were detected by electron microscopy. Although cyst-like expansion of the tubules was unclear, tubular atrophy was dominantly found in the distal tubule by cytokeratin 7 staining. Genetic analysis of the NPHP1 gene showed complete deletion of this gene, leading to a definitive diagnosis of NPHP. Conclusions NPHP is not merely a pediatric disease and is relatively high incidence in patients with adult onset end-stage of renal disease. In this case, typical histological abnormalities, such as cyst-like expansion of the tubular lesion, were not observed, and diagnosis was achieved by genetic analysis of the NPHP1 gene, which is responsible for the onset of NPHP. In patients with renal failure with tubular interstitial disease dominantly in the distal tubules, it is necessary to discriminate NPHP, even in adult cases.
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- 2021
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46. Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis
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Qiulei Hu, Jiayong Lai, Huamu Chen, Yong Cai, Zhihui Yue, Hongrong Lin, and Liangzhong Sun
- Subjects
nephronophthisis ,GEF-H1 ,RhoA ,cystogenesis ,inflammation ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Nephronophthisis (NPHP) is the most prevalent monogenic disease leading to end-stage renal failure in childhood. RhoA activation is involved in NPHP pathogenesis. This study explored the role of the RhoA activator guanine nucleotide exchange factor (GEF)-H1 in NPHP pathogenesis. We analyzed the expression and distribution of GEF-H1 in NPHP1 knockout (NPHP1KO) mice using Western blotting and immunofluorescence, followed by GEF-H1 knockdown. Immunofluorescence and renal histology were used to examine the cysts, inflammation, and fibrosis. A RhoA GTPase activation assay and Western blotting were used to detect the expression of downstream GTP-RhoA and p-MLC2, respectively. In NPHP1 knockdown (NPHP1KD) human kidney proximal tubular cells (HK2 cells), we detected the expressions of E-cadherin and α-smooth muscle actin (α-SMA). In vivo, increased expression and redistribution of GEF-H1, and higher levels of GTP-RhoA and p-MLC2 in renal tissue of NPHP1KO mice were observed, together with renal cysts, fibrosis, and inflammation. These changes were alleviated by GEF-H1 knockdown. In vitro, the expression of GEF-H1 and activation of RhoA were also increased, with increased expression of α-SMA and decreased E-cadherin. GEF-H1 knockdown reversed these changes in NPHP1KD HK2 cells. Thus, the GEF-H1/RhoA/MLC2 axis is activated in NPHP1 defects and may play a pivotal role in NPHP pathogenesis.
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- 2023
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47. Mitigation of portal fibrosis and cholestatic liver disease in ANKS6‐deficient livers by macrophage depletion.
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Airik, Merlin, McCourt, Blake, Ozturk, Tugba Tastemel, Huynh, Amy B., Zhang, Xiaoyi, Tometich, Justin T., Topaloglu, Rezan, Ozen, Hasan, Orhan, Diclehan, Nejak‐Bowen, Kari, Monga, Satdarshan P., Hand, Timothy W., Ozaltin, Fatih, and Airik, Rannar
- Abstract
Congenital hepatic fibrosis (CHF) is a developmental liver disease that is caused by mutations in genes that encode ciliary proteins and is characterized by bile duct dysplasia and portal fibrosis. Recent work has demonstrated that mutations in ANKS6 can cause CHF due to its role in bile duct development. Here, we report a novel ANKS6 mutation, which was identified in an infant presenting with neonatal jaundice due to underlying biliary abnormalities and liver fibrosis. Molecular analysis revealed that ANKS6 liver pathology is associated with the infiltration of inflammatory macrophages to the periportal fibrotic tissue and ductal epithelium. To further investigate the role of macrophages in CHF pathophysiology, we generated a novel liver‐specific Anks6 knockout mouse model. The mutant mice develop biliary abnormalities and rapidly progressing periportal fibrosis reminiscent of human CHF. The development of portal fibrosis in Anks6 KO mice coincided with the accumulation of inflammatory monocytes and macrophages in the mutant liver. Gene expression and flow cytometric analysis demonstrated the preponderance of M1‐ over M2‐like macrophages at the onset of fibrosis. A critical role for macrophages in promoting peribiliary fibrosis was demonstrated by depleting the macrophages with clodronate liposomes which effectively reduced inflammatory gene expression and fibrosis, and ameliorated tissue histology and biliary function in Anks6 KO livers. Together, this study demonstrates that macrophages play an important role in the initiation of liver fibrosis in ANKS6‐deficient livers and their therapeutic elimination may provide an avenue to mitigate CHF in patients. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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48. Compound heterozygous ADAMTS9 variants in Joubert syndrome-related disorders without renal manifestation.
- Author
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Matsushita, Hiroko Baber, Hiraide, Takuya, Hayakawa, Katsumi, Okano, Sozo, Nakashima, Mitsuko, Saitsu, Hirotomo, and Kato, Mitsuhiro
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- *
GENETIC variation , *JOUBERT syndrome , *SYMPTOMS , *POLYCYSTIC kidney disease , *RETINITIS pigmentosa , *KIDNEY diseases - Abstract
Ciliopathies are the outcomes of defects of primary cilia structures and functions which cause multisystemic developmental disorders, such as polycystic kidney disease, nephronophthisis, retinitis pigmentosa, Joubert syndrome (JS), and JS-related disorders (JSRD) with additional organ involvement including oral-facial-digital syndrome and so on. They often share common and unexpected phenotypic features. We report a 4-year-old-boy case with compound heterozygous variants of ADAMTS9. Unlike the cases with ADAMTS9 variants in the previous report, which identified that homozygous variants of ADAMTS9 were responsible for nephronophthisis-related ciliopathies in two cases, the current case did not have nephronophthisis nor renal dysfunction, and his clinical features, such as oculomotor apraxia, hypotonia, developmental delay, bifid tongue, and mild hypoplasia of cerebellar vermis indicated JSRD. The case suggested a possible association between the clinical presentation of JSRD and ADAMTS9 -related disease, and it shows a wide spectrum of ADAMTS9 phenotype. [ABSTRACT FROM AUTHOR]
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- 2022
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49. Temporal Profile of Kynurenine Pathway Metabolites in a Rodent Model of Autosomal Recessive Polycystic Kidney Disease.
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Pires, Ananda Staats, Gupta, Shabarni, Barton, Sean A., Wall, Roshana Vander, Tan, Vanessa, Benjamin Heng, Phillips, Jacqueline K., and Guillemin, Gilles J.
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- *
AUTOSOMAL recessive polycystic kidney , *KYNURENINE , *TRYPTOPHAN , *CHRONIC kidney failure , *TRP channels , *POLYCYSTIC kidney disease , *CYSTIC kidney disease - Abstract
Autosomal recessive polycystic kidney disease (ARPKD) is an early onset genetic disorder characterized by numerous renal cysts resulting in end stage renal disease. Our study aimed to determine if metabolic reprogramming and tryptophan (Trp) metabolism via the kynurenine pathway (KP) is a critical dysregulated pathway in PKD. Using the Lewis polycystic kidney (LPK) rat model of PKD and Lewis controls, we profiled temporal trends for KP metabolites in plasma, urine, and kidney tissues from 6- and 12-week-old mixed sex animals using liquid and gas chromatography, minimum n = 5 per cohort. A greater kynurenine (KYN) concentration was observed in LPK kidney and plasma of 12-week rats compared to age matched Lewis controls (P = .05). LPK kidneys also showed an age effect (P = .05) with KYN being greater in 12-week versus 6-week LPK. The metabolites xanthurenic acid (XA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HAA) were significantly greater in the plasma of 12-week LPK rats compared to age matched Lewis controls (P = .05). Plasma XA and 3-HK also showed an age effect (P = .05) being greater in 12-week versus 6-week LPK. We further describe a decrease in Trp levels in LPK plasma and kidney (strain effect P = .05). There were no differences in KP metabolites in urine between cohorts. Using the ratio of product and substrates in the KP, a significant age-strain effect (P = .05) was observed in the activity of the KYN/Trp ratio (tryptophan-2,3-dioxygenase [TDO] or indoleamine-2,3-dioxygenase [IDO] activity), kynurenine 3-monooxygenase (KMO), KAT A (kynurenine aminotransferase A), KAT B, total KAT, total KYNU (kynureninase), KYNU A, KYNU B, and total KYNU within LPK kidneys, supporting an activated KP. Confirmation of the activation of these enzymes will require verification through orthogonal techniques. In conclusion, we have demonstrated an up-regulation of the KP in alignment with progression of renal impairment in the LPK rat model, suggesting that KP activation may be a critical contributor to the pathobiology of PKD. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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50. Overexpression of smad7 inhibits the TGF-β/Smad signaling pathway and EMT in NPHP1-defective MDCK cells.
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Wu, Xiaohong, Wang, Haiyan, Chen, Huamu, Lin, Hongrong, Li, Min, Yue, Zhihui, and Sun, Liangzhong
- Subjects
- *
CELLULAR signal transduction , *EPITHELIAL-mesenchymal transition , *WESTERN immunoblotting , *PATHOGENESIS , *DISEASE progression - Abstract
Nephronophthisis (NPHP) is a kind of ciliopathy. Interstitial fibrosis occurs at the early stage of the disease. TGF-β/Smad is a key signaling pathway in regulating interstitial fibrosis and epithelial-mesenchymal transition (EMT). In this study, we explored the activation of the TGF-β/Smad signaling pathway and EMT in NPHP1-defective MDCK cells to further understand the pathogenesis of NPHP. NPHP1 -knockdown (NPHP1KD) MDCK cells were constructed by recombinant lentiviral short hairpin RNA, and NPHP1-knockout (NPHP1 KO) MDCK cells were constructed by using the CRISPR/Cas9 technique. The morphology and migration ability were observed under a microscope. Western blotting was used to detect the expression of E-cadherin, β-catenin, α-smooth muscle actin (α-SMA), fibroblast-specific protein-1(FSP1), TGF-β1, Smad2, Smad3, p-Smad3, Smad4 and Smad7. The localization of Smad3 was determined by immunofluorescence assay. NPHP1 KD and NPHP1KO MDCK cells were spindle-shaped and presented EMT-like changes. E-cadherin and β-catenin expression decreased, while α-SMA and FSP1 expression increased; the TGF-β/Smad signaling pathway was activated, Smad2, Smad3, p-Smad3 and Smad4 expression increased, Smad3 translocated to nuclear and Smad7 expression decreased compared with those in wild type MDCK cells. Overexpression of Smad7 reversed these changes to different degrees. Our results indicate that NPHP1 defects induce the activation of the TGF-β/Smad signaling pathway and EMT in MDCK cells. These factors may be implicated in the pathogenesis of interstitial fibrosis in NPHP. • NPHP1 defects induce the activation of the TGF-β/Smad signaling pathway. • NPHP1 defects induce EMT in MDCK cells. • TGF-β/Smad signaling may be related with the pathogenesis of interstitial fibrosis in NPHP. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
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