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Jens Christian König, Andrea Titieni, Martin Konrad
Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome, and hepatocyte nuclear factor-1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype-phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases...
2018: Frontiers in Pediatrics
Katie Weihbrecht, Wesley A Goar, Calvin S Carter, Val C Sheffield, Seongjin Seo
Nephronophthisis-related ciliopathies (NPHP-RC) are a group of disorders that present with end-stage renal failure in childhood/adolescence, kidney cysts, retinal degeneration, and cerebellar hypoplasia. One disorder that shares clinical features with NPHP-RC is Bardet-Biedl Syndrome (BBS). Serologically defined colon cancer antigen 8 (SDCCAG8; also known as NPHP10 and BBS16) is an NPHP gene that is also associated with BBS. To better understand the patho-mechanisms of NPHP and BBS caused by loss of SDCCAG8 function, we characterized an SDCCAG8 mouse model (Sdccag8Tn(sb-Tyr)2161B...
2018: PloS One
Oliver Oey, Padmashree Rao, Magdalena Luciuk, Carly Mannix, Natasha M Rogers, Priyanka Sagar, Annette Wong, Gopala Rangan
Dimethyl fumarate is an FDA-approved oral immunomodulatory drug with anti-inflammatory properties that induces the upregulation of the anti-oxidant transcription factor, nuclear factor erythroid-derived factor 2. The aim of this study was to determine the efficacy of dimethyl fumarate on interstitial inflammation and renal cyst growth in a preclinical model of nephronophthisis. Four-week-old female Lewis polycystic kidney disease (a genetic ortholog of human nephronophthisis-9) rats received vehicle (V), 10 mg/kg (D10) or 30 mg/kg (D30) ( n = 8-9 each) dimethyl fumarate in drinking water for eight weeks...
January 1, 2018: Experimental Biology and Medicine
Raluca Isac, Rodica Costa, Dorela CodruŢa Lăzureanu, Cristina Ioana Olariu, Adriana Milena Muntean, Cornel Olimpiu Aldea, Gabriela Simona Doroş, Mihai Gafencu
Post-transplant lymphoproliferative disorder (PTLD) is defined as a heterogeneous group of lymphoid and plasmocytic proliferations with variable malignant potential. They often arise in immunocompromised post solid organ transplant (SOT) patients linked with Epstein-Barr virus (EBV) infection. Clinical manifestations include fever, lymphadenopathy and organ involvement. Diagnosis of PTLD requires morphopathological tissue examination. Treatment of EBV-related PTLD in SOT patients includes immunosuppressive (IS) agents' reduction, use of antiviral medication, anti-B-lymphocyte antibodies and chemotherapy for high-risk patients...
2017: Romanian Journal of Morphology and Embryology, Revue Roumaine de Morphologie et Embryologie
M Rasmussen, L Sunde, M L Nielsen, M Ramsing, A Petersen, T D Hjortshøj, T E Olsen, A Tabor, J M Hertz, I Johnsen, L Sperling, O B Petersen, U B Jensen, F G Møller, M B Petersen, D L Lildballe
Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next-generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in-house-designed kidney-gene panel. In families where candidate variants were not identified, whole-exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel...
November 30, 2017: Clinical Genetics
Daisuke Takada, Akinari Sekine, Junko Yabuuchi, Yuta Kogure, Toshiharu Ueno, Masayuki Yamanouchi, Keiichi Sumida, Tatsuya Suwabe, Noriko Hayami, Junichi Hoshino, Kenmei Takaichi, Keiichi Kinowaki, Takeshi Fujii, Kenichi Ohashi, Takayasu Mori, Eisei Sohara, Shinichi Uchida, Yoshifumi Ubara
We investigated a 25-year-old Japanese man who had polycystic kidneys and end-stage renal failure without a positive family history. Ultrasonography revealed enlarged kidneys with increased echogenicity and multiple cystic lesions. MRI showed replacement of both kidneys by cystic lesions without definite walls. Renal biopsy demonstrated interstitial fibrosis, especially at the corticomedullary junction. The residual tubular system showed starfish-like disruption. Tubules with cystic dilation were mainly the distal loop of Henle and the distal tubules since immunohistochemical staining was positive for cytokeratin 7 (the distal loop of Henle and the distal tubule) and Tamm-Horsfall protein (the distal loop of Henle), while being negative for aquaporin 3 (the collecting duct) and CD10 (proximal tubule)...
November 22, 2017: Clinical Nephrology
Leah R Fleming, Daniel A Doherty, Melissa A Parisi, Ian A Glass, Joy Bryant, Roxanne Fischer, Baris Turkbey, Peter Choyke, Kailash Daryanani, Meghana Vemulapalli, James C Mullikin, May Christine Malicdan, Thierry Vilboux, John A Sayer, William A Gahl, Meral Gunay-Aygun
BACKGROUND AND OBJECTIVES: Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing...
December 7, 2017: Clinical Journal of the American Society of Nephrology: CJASN
Jens König, Birgitta Kranz, Sabine König, Karl Peter Schlingmann, Andrea Titieni, Burkhard Tönshoff, Sandra Habbig, Lars Pape, Karsten Häffner, Matthias Hansen, Anja Büscher, Martin Bald, Heiko Billing, Raphael Schild, Ulrike Walden, Tobias Hampel, Hagen Staude, Magdalena Riedl, Norbert Gretz, Martin Lablans, Carsten Bergmann, Friedhelm Hildebrandt, Heymut Omran, Martin Konrad
BACKGROUND AND OBJECTIVES: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes ( NPHP1 to -20 ) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online-based registry (www...
December 7, 2017: Clinical Journal of the American Society of Nephrology: CJASN
Joanna Walczak-Sztulpa, Anna Wawrocka, Anna Swiader-Lesniak, Magdalena Socha, Aleksander Jamsheer, Dorota Drozdz, Anna Latos-Bielenska, Katarzyna Zachwieja
BACKGROUND: Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy first described by Judith Sensenbrenner in 1975. CED is a complex disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. The clinical symptoms are variable and the CED phenotype may present intrafamilial and interfamilial differences. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disease...
November 14, 2017: Birth Defects Research
Nalini H Kulkarni, Rosamund C Smith, Bonnie L Blazer-Yost
Type II nephronophthisis (NPHP2) is an autosomal recessive renal cystic disorder characterized by mutations in the inversin gene. Humans and mice with mutations in inversin have enlarged cystic kidneys that may be due to fluid accumulation resulting from altered ion transport. To address this, transepithelial ion transport was measured in shRNA mediated inversin-depleted mouse cortical collecting duct (mCCD) cells. Loss of inversin decreased the basal ion flux in mCCD cells compared to controls. Depletion of inversin decreased vasopressin-induced Na+ absorption, but did not alter Cl- secretion by mCCD cells...
October 4, 2017: American Journal of Physiology. Cell Physiology
Shalabh Srivastava, Simon A Ramsbottom, Elisa Molinari, Sumaya Alkanderi, Andrew Filby, Kathryn White, Charline Henry, Sophie Saunier, Colin G Miles, John A Sayer
Joubert syndrome (JBTS) is the archetypal ciliopathy caused by mutation of genes encoding ciliary proteins leading to multi-system phenotypes, including a cerebello-retinal-renal syndrome. JBTS is genetically heterogeneous, however mutations in CEP290 are a common underlying cause. The renal manifestation of JBTS is a juvenile-onset cystic kidney disease, known as nephronophthisis, typically progressing to end-stage renal failure within the first two decades of life, thus providing a potential window for therapeutic intervention...
September 11, 2017: Human Molecular Genetics
Uzma Abdullah, Muhammad Farooq, Ambrin Fatima, Wasima Tauseef, Yasra Sarwar, Mmh Nuri, Niels Tommerup, Shahid M Baig
We present a case of a foetal sonographic finding of hyper-echogenic kidneys, which led to a strategic series of genetic tests and identified a homozygous mutation (c.424C > T, p. R142*) in the NPHP3 gene. Our study provides a rare presentation of NPHP3-related ciliopathy and adds to the mutation spectrum of the gene, being the first one from Pakistani population. With a thorough literature review, it also advocates for molecular assessment of ciliopathies to improve risk estimate for future pregnancies, and identify predisposed asymptomatic carriers...
October 2017: Nephrology
Xiaoyu Shi, Galo Garcia, Julie C Van De Weghe, Ryan McGorty, Gregory J Pazour, Dan Doherty, Bo Huang, Jeremy F Reiter
Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its membrane. We defined the three-dimensional arrangement of key proteins in the transition zone using two-colour stochastic optical reconstruction microscopy (STORM). NPHP and MKS complex components form nested rings comprised of nine-fold doublets. JBTS-associated mutations in RPGRIP1L or TCTN2 displace certain transition-zone proteins...
October 2017: Nature Cell Biology
Md Monirujjaman, Jessay G Devassy, Tamio Yamaguchi, Nikhil Sidhu, Masanori Kugita, Melissa Gabbs, Shizuko Nagao, Jing Zhou, Amir Ravandi, Harold M Aukema
Cystic kidney diseases are characterized by multiple renal cysts and are the leading cause of inherited renal disease. Oxylipins are bioactive lipids derived from fatty acids formed via cyclooxygenase, lipoxygenase and cytochrome P450 activity, and are important regulators of renal health and disease. Oxylipins are altered in nephronophthisis, a type of cystic kidney disease. To further investigate and to determine whether other cystic renal diseases share these abnormalities, a targeted lipidomic analysis of renal oxylipins was performed in orthologous models of autosomal dominant polycystic kidney disease 1 (Mx1Cre(+)Pkd1(flox/flox) mouse) and 2 (Pkd2(ws25/-) mouse), autosomal recessive polycystic kidney disease (PCK rat) and nephronophthisis (jck/jck mouse)...
December 2017: Biochimica et Biophysica Acta
Daisuke Takao, Liang Wang, Allison Boss, Kristen J Verhey
The motility and signaling functions of the primary cilium require a unique protein and lipid composition that is determined by gating mechanisms localized at the base of the cilium. Several protein complexes localize to the gating zone and may regulate ciliary protein composition; however, the mechanisms of ciliary gating and the dynamics of the gating components are largely unknown. Here, we used the BiFC (bimolecular fluorescence complementation) assay and report for the first time on the protein-protein interactions that occur between ciliary gating components and transiting cargoes during ciliary entry...
August 7, 2017: Current Biology: CB
T Tkemaladze, G Melikishvili, V Kherkheulidze, A Melikishvili, T Davitaia
Human ciliopathies are a class of multi-organ genetic disorders caused by defects of proteins expressed at the primary cilium, an organelle present on the cell surface of almost all cell types. Thus far, dozens of causative genes for ciliopathies have been identified and many of them are known to cause allelic disease. Of particular interest is the TMEM67 gene, encoding the transmembrane protein meckelin. The involvement of the mutant TMEM67 gene is known to be associated with a broad range of clinical presentations, namely Joubert syndrome 6 (JBTS6), nephronophthisis 11 (NPHP11), Bardet-Biedel syndrome (BBS), COACH syndrome, and lethal Meckel syndrome type 3 (MKS3)...
June 2017: Georgian Medical News
Takahisa Yoshikawa, Koichi Kamei, Hiroko Nagata, Ken Saida, Mai Sato, Masao Ogura, Shuichi Ito, Osamu Miyazaki, Maki Urushihara, Shuji Kondo, Noriko Sugawara, Kiyonobu Ishizuka, Yuko Hamasaki, Seiichiro Shishido, Naoya Morisada, Kazumoto Iijima, Michio Nagata, Takako Yoshioka, Kentaro Ogata, Kenji Ishikura
WDR19 has been reported as a causative gene of nephronophthisis-related ciliopathies. Patients with WDR19 mutations can show various extrarenal manifestations such as skeletal disorders, Caroli disease, and retinal dystrophy, and typically display nephronophthisis as a renal phenotype. However, there is limited information on the renal phenotypes of patients with WDR19 mutations. We report two Japanese infants with Sensenbrenner syndrome caused by WDR19 mutations who demonstrated different features in renal ultrasound and histopathological results, despite several common extrarenal manifestations...
July 2017: Nephrology
Gui-Yang Jiang, Yong Zhang, Xiu-Peng Zhang, Xu-Yong Lin, Juan-Han Yu, En-Hua Wang
Inversin, encoded by NPHP2, is one of the 10 NPHP proteins known to be involved in nephronophthisis (an autosomal recessive cystic kidney). Although the previous reports showed that inversin played an important role in embryonic development and renal diseases, its function in cancer was not revealed clearly so far. As measured by immunohistochemical staining, inversin was highly expressed in the cytoplasm of lung cancer samples (63.4%, 161/254) compared with adjacent normal lung tissues (22.0%, 11/50, p < 0...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Fateme Shamekhi Amiri, Ariana Kariminejad
Nephronophthisis, an autosomal recessive kidney disease, represents the most frequent genetic cause of end-stage kidney disease in the first three decades of life. A 27-year-old male was presented with gait imbalance, sever pruritus since 10 days prior time of admission. In past medical history, he had bilateral cataract, torsional nystagmus, and bilateral optic nerve atrophy since 2 years of age. He was also mentioned history of multinodular goiter with dysfunctional thyroid state since 2 years before admission...
May 2017: CEN Case Reports
Pauline Scherdel, Rachel Reynaud, Christine Pietrement, Jean-François Salaün, Marc Bellaïche, Michel Arnould, Bertrand Chevallier, Hugues Piloquet, Emmanuel Jobez, Jacques Cheymol, Emmanuelle Bichara, Barbara Heude, Martin Chalumeau
BACKGROUND: Growth monitoring of apparently healthy children aims at early detection of serious conditions through the use of both clinical expertise and algorithms that define abnormal growth. Optimization of growth monitoring requires standardization of the definition of abnormal growth, and the selection of the priority target conditions is a prerequisite of such standardization. OBJECTIVE: To obtain a consensus about the priority target conditions for algorithms monitoring children's growth...
2017: PloS One
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