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L Z Sun, H R Lin, Z H Yue, H Y Wang, X Y Jiang, H J Tong, M Li, W G Wang, Y K Mou, F Yang, T Liu, H M Chen
Objective: To explore the clinical features and pathogenic gene mutation of juvenile nephronophthisis (NPHP) in Chinese patients. Method: Clinical data and blood samples of 27 juvenile NPHP patients from 25 families who were initially clinically diagnosed in six hospitals in Guangdong province were collected. NPHP1 homozygous deletions were detected in all patients. Sequencing of NPHP1 gene was performed when homozygous deletions were not found in patients without eye involvement. In patients with eye involvement, NPHP5 sequencing was carried out initially and subsequently NPHP10 gene and NPHP1 when there were no NPHP5 gene mutation found...
November 2, 2016: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Daniela A Braun, Friedhelm Hildebrandt
Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited diseases that affect genes encoding proteins that localize to primary cilia or centrosomes. With few exceptions, ciliopathies are inherited in an autosomal recessive manner, and affected individuals manifest early during childhood or adolescence. NPHP-RC are genetically very heterogeneous, and, currently, mutations in more than 90 genes have been described as single-gene causes. The phenotypes of NPHP-RC are very diverse, and include cystic-fibrotic kidney disease, brain developmental defects, retinal degeneration, skeletal deformities, facial dimorphism, and, in some cases, laterality defects, and congenital heart disease...
October 28, 2016: Cold Spring Harbor Perspectives in Biology
Baris Buke, Emre Canverenler, Göksun İpek, Semiha Canverenler, Hatice Akkaya
Joubert syndrome (JS) and related disorders (JSRD) are a group of multiple congenital anomaly syndromes in which the diagnostic hallmark is the molar tooth sign (MTS), a complex midbrain malformation visible on brain imaging. Detection of the MTS should be followed by a diagnostic protocol to assess multi-organ involvement. The incidence of JSRD ranges between 1/80,000 and 1/100,000 live births, although these values may represent an underestimate. The neurological components of JSRD include hypotonia, ataxia, intellectual disability, abnormal eye movements, and neonatal breathing problems...
October 26, 2016: Journal of Medical Ultrasonics
Chen-Jei Hong, Bruce A Hamilton
Zfp423 encodes a 30-zinc finger transcription factor that intersects several canonical signaling pathways. Zfp423 mutations result in ciliopathy-related phenotypes, including agenesis of the cerebellar vermis in mice and Joubert syndrome (JBTS19) and nephronophthisis (NPHP14) in humans. Unlike most ciliopathy genes, Zfp423 encodes a nuclear protein and its developmental expression is complex, leading to alternative proposals for cellular mechanisms. Here we show that Zfp423 is expressed by cerebellar granule cell precursors, that loss of Zfp423 in these precursors leads to cell-intrinsic reduction in proliferation, loss of response to Shh, and primary cilia abnormalities that include diminished frequency of both Smoothened and IFT88 localization...
October 2016: PLoS Genetics
Maleeha Maria, Ideke J C Lamers, Miriam Schmidts, Muhammad Ajmal, Sulman Jaffar, Ehsan Ullah, Bilal Mustafa, Shakeel Ahmad, Katia Nazmutdinova, Bethan Hoskins, Erwin van Wijk, Linda Koster-Kamphuis, Muhammad Imran Khan, Phil L Beales, Frans P M Cremers, Ronald Roepman, Maleeha Azam, Heleen H Arts, Raheel Qamar
Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder that is both genetically and clinically heterogeneous. To date 19 genes have been associated with BBS, which encode proteins active at the primary cilium, an antenna-like organelle that acts as the cell's signaling hub. In the current study, a combination of mutation screening, targeted sequencing of ciliopathy genes associated with BBS, and whole-exome sequencing was used for the genetic characterization of five families including four with classic BBS symptoms and one BBS-like syndrome...
October 6, 2016: Scientific Reports
Metta B Pratt, Joshua S Titlow, Ilan Davis, Amy R Barker, Helen R Dawe, Jordan W Raff, Helio Roque
Cilia are conserved organelles that have important motility, sensory and signalling roles. The transition zone (TZ) at the base of the cilium is crucial for cilia function, and defects in several TZ proteins are associated with human congenital ciliopathies such as nephronophthisis (NPHP) and Meckel-Gruber syndrome (MKS). In several species, MKS and NPHP proteins form separate complexes that cooperate with Cep290 to assemble the TZ, but flies seem to lack core components of the NPHP module. We show that MKS proteins in flies are spatially separated from Cep290 at the TZ, and that flies mutant for individual MKS genes fail to recruit other MKS proteins to the TZ, whereas Cep290 seems to be recruited normally...
October 15, 2016: Journal of Cell Science
Shinsuke Niwa
Defects in cilia cause a spectrum of diseases known as ciliopathies. Nephronophthisis, a ciliopathy, is the most common genetic cause of renal disease. Here, I cloned and analysed a nephronophthisis-related gene ift-139 in Caenorhabditis elegans. ift-139 was exclusively expressed in ciliated neurons in C. elegans. Genetic and cellular analyses suggest that ift-139 plays a role in retrograde intraflagellar transport and is required for cilia formation. A homologous point mutation that causes ciliopathy disrupted the function of ift-139 in C...
2016: Scientific Reports
Hee Gyung Kang, Hyun Kyung Lee, Yo Han Ahn, Je-Gun Joung, Jaeyong Nam, Nayoung K D Kim, Jung Min Ko, Min Hyun Cho, Jae Il Shin, Joon Kim, Hye Won Park, Young Seo Park, Il-Soo Ha, Woo Yeong Chung, Dae-Yeol Lee, Su Young Kim, Woong Yang Park, Hae Il Cheong
Nephronophthisis-related ciliopathy (NPHP-RC) is a common genetic cause of end-stage renal failure during childhood and adolescence and exhibits an autosomal recessive pattern of inheritance. Genetic diagnosis is quite limited owing to genetic heterogeneity in NPHP-RC. We designed a novel approach involving the step-wise screening of Sanger sequencing and targeted exome sequencing for the genetic diagnosis of 55 patients with NPHP-RC. First, five NPHP-RC genes were analyzed by Sanger sequencing in phenotypically classified patients...
2016: Experimental & Molecular Medicine
Werner Keenswijk, Johan Vande Walle
A 4-year-old boy was referred to the nephrologist with daytime urinary incontinence and suspicion of an overactive bladder. At the age of 17 months he had been referred to the pediatric endocrinologist because of polyuria and polydipsia in order to exclude diabetes insipidus. Repeated water deprivation tests and a magnetic resonance imaging scan of the brain were normal. Diabetes insipidus was excluded, and primary polydipsia was thought to be most likely since diabetes mellitus also had been excluded. At the current presentation, he drank up to 3 L a day and quite often had wet diapers...
June 27, 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Cecinio C Ronquillo, Christin Hanke-Gogokhia, Monica P Revelo, Jeanne M Frederick, Li Jiang, Wolfgang Baehr
Null mutations in the human IQCB1/NPHP5 (nephrocystin-5) gene that encodes NPHP5 are the most frequent cause of Senior-Løken syndrome, a ciliopathy that is characterized by Leber congenital amaurosis and nephronophthisis. We generated germline Nphp5 knockout mice by placing a β-Geo gene trap in intron 4, thereby truncating NPHP5 at Leu87 and removing all known functional domains. At eye opening, Nphp5(-/-) mice exhibited absence of scotopic and photopic electroretinogram responses, a phenotype that resembles Leber congenital amaurosis...
June 21, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Rannar Airik, Markus Schueler, Merlin Airik, Jang Cho, Kelsey A Ulanowicz, Jonathan D Porath, Toby W Hurd, Simon Bekker-Jensen, Jacob M Schrøder, Jens S Andersen, Friedhelm Hildebrandt
Recessive mutations in the SDCCAG8 gene cause a nephronophthisis-related ciliopathy with Bardet-Biedl syndrome-like features in humans. Our previous characterization of the orthologous Sdccag8gt/gt mouse model recapitulated the retinal-renal disease phenotypes and identified impaired DNA damage response signaling as an underlying disease mechanism in the kidney. However, several other phenotypic and mechanistic features of Sdccag8gt/gt mice remained unexplored. Here we show that Sdccag8gt/gt mice exhibit developmental and structural abnormalities of the skeleton and limbs, suggesting impaired Hedgehog (Hh) signaling...
2016: PloS One
Futoshi Suizu, Noriyuki Hirata, Kohki Kimura, Tatsuma Edamura, Tsutomu Tanaka, Satoko Ishigaki, Thoria Donia, Hiroko Noguchi, Toshihiko Iwanaga, Masayuki Noguchi
A primary cilium is a microtubule-based sensory organelle that plays an important role in human development and disease. However, regulation of Akt in cilia and its role in ciliary development has not been demonstrated. Using yeast two-hybrid screening, we demonstrate that Inversin (INVS) interacts with Akt. Mutation in the INVS gene causes nephronophthisis type II (NPHP2), an autosomal recessive chronic tubulointerstitial nephropathy. Co-immunoprecipitation assays show that Akt interacts with INVS via the C-terminus...
June 15, 2016: EMBO Journal
Dongmei Lu, Alysha Rauhauser, Binghua Li, Chongyu Ren, Kayla McEnery, Jili Zhu, Moumita Chaki, Komal Vadnagara, Sarah Elhadi, Anton M Jetten, Peter Igarashi, Massimo Attanasio
Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3a knockout mouse is an established non-orthologous mouse model of cystic kidney disease. Conditional inactivation of Kif3a in kidney tubular cells results in loss of primary cilia and rapid cyst growth. Conversely, loss of function of the gene GLIS2/NPHP7 causes progressive kidney atrophy, interstitial inflammatory infiltration, and fibrosis...
June 2016: Kidney International
Christina Bracken, Philippe Beauverger, Olivier Duclos, Ryan J Russo, Kelly A Rogers, Hervé Husson, Thomas A Natoli, Steven R Ledbetter, Philip Janiak, Oxana Ibraghimov-Beskrovnaya, Nikolay O Bukanov
Polycystic kidney diseases (PKDs) are genetic diseases characterized by renal cyst formation with increased cell proliferation, apoptosis, and transition to a secretory phenotype at the expense of terminal differentiation. Despite recent progress in understanding PKD pathogenesis and the emergence of potential therapies, the key molecular mechanisms promoting cystogenesis are not well understood. Here, we demonstrate that mechanisms including endoplasmic reticulum stress, oxidative damage, and compromised mitochondrial function all contribute to nephronophthisis-associated PKD...
June 1, 2016: American Journal of Physiology. Renal Physiology
Hervé Husson, Sarah Moreno, Laurie A Smith, Mandy M Smith, Ryan J Russo, Rose Pitstick, Mikhail Sergeev, Steven R Ledbetter, Nikolay O Bukanov, Monica Lane, Kate Zhang, Katy Billot, George Carlson, Jagesh Shah, Laurent Meijer, David R Beier, Oxana Ibraghimov-Beskrovnaya
Polycystic kidney diseases (PKDs) comprise a subgroup of ciliopathies characterized by the formation of fluid-filled kidney cysts and progression to end-stage renal disease. A mechanistic understanding of cystogenesis is crucial for the development of viable therapeutic options. Here, we identify CDK5, a kinase active in post mitotic cells, as a new and important mediator of PKD progression. We show that long-lasting attenuation of PKD in the juvenile cystic kidneys (jck) mouse model of nephronophthisis by pharmacological inhibition of CDK5 using either R-roscovitine or S-CR8 is accompanied by sustained shortening of cilia and a more normal epithelial phenotype, suggesting this treatment results in a reprogramming of cellular differentiation...
April 5, 2016: Human Molecular Genetics
Liru Qiu, Jianhua Zhou
BACKGROUND: LAMB2 mutations cause Pierson syndrome (OMIM 609049), an autosomal recessive genetic disease typically characterized by congenital nephrotic syndrome (CNS) and early onset renal failure, as well as bilateral microcoria. NPHP1 mutations cause familial juvenile nephronophthisis type 1 (NPHP1, OMIM 256100), another autosomal recessive renal disease that usually occurs years after birth. Both Pierson syndrome and nephronophthisis cause end-stage renal disease and rare kidney diseases in children...
March 22, 2016: BMC Pediatrics
Chunmei Li, Victor L Jensen, Kwangjin Park, Julie Kennedy, Francesc R Garcia-Gonzalo, Marta Romani, Roberta De Mori, Ange-Line Bruel, Dominique Gaillard, Bérénice Doray, Estelle Lopez, Jean-Baptiste Rivière, Laurence Faivre, Christel Thauvin-Robinet, Jeremy F Reiter, Oliver E Blacque, Enza Maria Valente, Michel R Leroux
Cilia have a unique diffusion barrier ("gate") within their proximal region, termed transition zone (TZ), that compartmentalises signalling proteins within the organelle. The TZ is known to harbour two functional modules/complexes (Meckel syndrome [MKS] and Nephronophthisis [NPHP]) defined by genetic interaction, interdependent protein localisation (hierarchy), and proteomic studies. However, the composition and molecular organisation of these modules and their links to human ciliary disease are not completely understood...
March 2016: PLoS Biology
Tomohiko Yamamura, Naoya Morisada, Kandai Nozu, Shogo Minamikawa, Shingo Ishimori, Daisaku Toyoshima, Takeshi Ninchoji, Masato Yasui, Mariko Taniguchi-Ikeda, Ichiro Morioka, Koichi Nakanishi, Hisahide Nishio, Kazumoto Iijima
BACKGROUND: Nephronophthisis-related ciliopathies (NPHP-RC) are a frequent cause of renal failure for children and adolescents. Although diagnosing these diseases clinically is difficult, a comprehensive genetic screening approach of targeted resequencing can uncover the genetic background in this complicated family of diseases. METHODS: We studied three Japanese female patients with renal insufficiency from non-consanguineous parents. A renal biopsy for clinical reasons was not performed...
March 11, 2016: Clinical and Experimental Nephrology
Gemma Bullich, Iván Vargas, Daniel Trujillano, Santiago Mendizábal, Juan Alberto Piñero-Fernández, Gloria Fraga, José García-Solano, José Ballarín, Xavier Estivill, Roser Torra, Elisabet Ars
BACKGROUND: The TTC21B gene was initially described as causative of nephronophthisis (NPHP). Recently, the homozygous TTC21B p.P209L mutation has been identified in families with focal segmental glomerulosclerosis (FSGS) and tubulointerstitial lesions. Heterozygous TTC21B variants have been proposed as genetic modifiers in ciliopathies. We aimed to study the causative and modifying role of the TTC21B gene in glomerular and cystic kidney diseases. METHODS: Mutation analysis of the TTC21B gene was performed by massive parallel sequencing...
March 2, 2016: Nephrology, Dialysis, Transplantation
Svetlana V Masyukova, Dawn E Landis, Scott J Henke, Corey L Williams, Jay N Pieczynski, Kelly N Roszczynialski, Jannese E Covington, Erik B Malarkey, Bradley K Yoder
Nephronophthisis (NPHP) is a ciliopathy in which genetic modifiers may underlie the variable penetrance of clinical features. To identify modifiers, a screen was conducted on C. elegans nphp-4(tm925) mutants. Mutations in ten loci exacerbating nphp-4(tm925) ciliary defects were obtained. Four loci have been identified, three of which are established ciliopathy genes mks-1, mks-2, and mks-5. The fourth allele (yhw66) is a missense mutation (S316F) in OSM-3, a kinesin required for cilia distal segment assembly...
February 2016: PLoS Genetics
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