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https://www.readbyqxmd.com/read/29703621/-pkhd1-mutations-in-autosomal-recessive-polycystic-kidney-disease-arpkd-genotype-phenotype-correlations-from-a-series-of-308-cases-to-improve-prenatal-counselling
#1
Suzy Hamo, Justine Bacchetta, Aurélia Bertholet-Thomas, Bruno Ranchin, Pierre Cochat, Laurence Michel-Calemard
OBJECTIVES: ARPKD is a recessive rare disease due to PKHD1 mutation. The main objective of the study was to characterize the phenotypic variability according to the different types of PKHD1 mutations. METHODS: This study was performed in 308 ARPKD patients with a genetic diagnosis from our genetic center. Related physicians provided minimal clinical and biological data. RESULTS: Patients were divided into three genotypic groups: the first group (G1; n=65) consisted of patients with two truncating mutations, the second group (G2; n=117) of patients with one truncating and one non-truncating mutation, and the third group (G3; n=126) of patients with two non-truncating mutations...
April 24, 2018: Néphrologie & Thérapeutique
https://www.readbyqxmd.com/read/29643536/-genetic-diagnosis-of-caroli-syndrome-with-autosomal-recessive-polycystic-kidney-disease-a-case-report-and-literature-review
#2
X Y Yang, L P Zhu, X Q Liu, C Y Zhang, Y Yao, Y Wu
This case report is about one genetically specified diagnosed infant case of Caroli syndrome with autosomal recessive polycystic kidney disease (ARPKD) in China. The patient in this case report was an eight-month infant boy with an atypical onset and the main clinical manifestation was non-symptomatic enlargement of the liver and kidneys. The imaging study demonstrated a diffused cystic dilatation of intrahepatic bile ducts as well as polycystic changes in bilateral kidneys. The basic blood biochemical tests indicated a normal hepatorenal function...
April 18, 2018: Beijing da Xue Xue Bao. Yi Xue Ban, Journal of Peking University. Health Sciences
https://www.readbyqxmd.com/read/29520754/kidney-enlargement-and-multiple-liver-cyst-formation-implicate-mutations-in-pkd1-2-in-adult-sporadic-polycystic-kidney-disease
#3
T Fujimaru, T Mori, A Sekine, S Mandai, M Chiga, H Kikuchi, F Ando, Y Mori, N Nomura, S Iimori, S Naito, T Okado, T Rai, J Hoshino, Y Ubara, S Uchida, E Sohara
Distinguishing autosomal-dominant polycystic kidney disease (ADPKD) from other inherited renal cystic diseases in patients with adult polycystic kidney disease and no family history is critical for correct treatment and appropriate genetic counseling. However, for patients with no family history, there are no definitive imaging findings that provide an unequivocal ADPKD diagnosis. We analyzed 53 adult polycystic kidney disease patients with no family history. Comprehensive genetic testing was performed using capture-based next-generation sequencing for 69 genes currently known to cause hereditary renal cystic diseases including ADPKD...
March 9, 2018: Clinical Genetics
https://www.readbyqxmd.com/read/29455316/investigation-of-major-genetic-alterations-in-neuroblastoma
#4
Régis Afonso Costa, Héctor N Seuánez
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. This malignancy shows a wide spectrum of clinical outcome and its prognosis is conditioned by manifold biological and genetic factors. We investigated the tumor genetic profile and clinical data of 29 patients with NB by multiplex ligation-dependent probe amplification (MLPA) to assess therapeutic risk. In 18 of these tumors, MYCN status was assessed by fluorescence in situ hybridization (FISH). Copy number variation was also determined for confirming MLPA findings in two 6p loci...
February 17, 2018: Molecular Biology Reports
https://www.readbyqxmd.com/read/29420817/glutamine-metabolism-via-glutaminase-1-in-autosomal-dominant-polycystic-kidney-disease
#5
Irfana Soomro, Ying Sun, Zhai Li, Lonnette Diggs, Georgia Hatzivassiliou, Ajit G Thomas, Rana Rais, Barbara S Slusher, Stefan Somlo, Edward Y Skolnik
Background: Metabolism of glutamine by glutaminase 1 (GLS1) plays a key role in tumor cell proliferation via the generation of ATP and intermediates required for macromolecular synthesis. We hypothesized that glutamine metabolism also plays a role in proliferation of autosomal-dominant polycystic kidney disease (ADPKD) cells and that inhibiting GLS1 could slow cyst growth in animal models of ADPKD. Methods: Primary normal human kidney and ADPKD human cyst-lining epithelial cells were cultured in the presence or absence of two pharmacologic inhibitors of GLS1, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) and CB-839, and the effect on proliferation, cyst growth in collagen and activation of downstream signaling pathways were assessed...
February 5, 2018: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/29402207/congenital-hepatic-fibrosis-in-a-purebred-spanish-horse-foal-pathology-and-genetic-studies-on-pkhd1-gene-mutations
#6
Jéssica Molín, Javier Asín, Arantzazu Vitoria, Arianne Sanz, Marina Gimeno, Antonio Romero, Javier Sánchez, Pedro Pinczowski, Francisco J Vázquez, Clementina Rodellar, Lluís Luján
A 1-month-old Purebred Spanish Horse (PSH) foal presented with progressive hepatic failure culminating in death. Hepatic lesions were consistent with congenital hepatic fibrosis (CHF). Genetic studies in the PKHD1 gene in the affected foal revealed that it was heterozygous for the 2 previously described single-nucleotide polymorphisms (SNPs) linked to CHF in Swiss Franches-Montagnes (SFM) horses. In addition, 2 novel mutations were detected, the foal being homozygous for one of them and heterozygous for the other...
May 2018: Veterinary Pathology
https://www.readbyqxmd.com/read/29327352/ultrasound-findings-provide-clues-to-investigate-founder-mutations-expressed-as-runs-of-homozygosity-in-chromosomal-microarray-studies
#7
Hagit Daum, Israela Lerer, Ayala Frumkin, Daniel Rosenak, Nili Yanai, Shay Porat, Simcha Yagel, Vardiella Meiner
OBJECTIVES: Chromosomal microarray analysis is effectively applied prenatally to detect copy number changes. Single nucleotide polymorphism (SNP) probes included in the microarray platform can detect regions of excessive homozygosity and identical-by-descent genomic stretches. The utility of the latter as part of prenatal diagnosis is not well established. Recessive founder mutations are well recognized within distinct ethnic groups. Combining these data with prenatal sonography provides accurate focused molecular diagnoses quickly...
January 2018: Prenatal Diagnosis
https://www.readbyqxmd.com/read/29158418/a-novel-pkhd1-mutation-interacts-with-the-nonobese-diabetic-genetic-background-to-cause-autoimmune-cholangitis
#8
Wenting Huang, Daniel B Rainbow, Yuehong Wu, David Adams, Pranavkumar Shivakumar, Leah Kottyan, Rebekah Karns, Bruce Aronow, Jorge Bezerra, M Eric Gershwin, Laurence B Peterson, Linda S Wicker, William M Ridgway
We previously reported that NOD.c3c4 mice develop spontaneous autoimmune biliary disease (ABD) with anti-mitochondrial Abs, histopathological lesions, and autoimmune T lymphocytes similar to human primary biliary cholangitis. In this article, we demonstrate that ABD in NOD.c3c4 and related NOD ABD strains is caused by a chromosome 1 region that includes a novel mutation in polycystic kidney and hepatic disease 1 ( Pkhd1 ). We show that a long terminal repeat element inserted into intron 35 exposes an alternative polyadenylation site, resulting in a truncated Pkhd1 transcript...
January 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29140564/%C3%AE-catenin-and-il-1%C3%AE-dependent-cxcl10-production-drives-progression-of-disease-in-a-mouse-model-of-congenital-hepatic-fibrosis
#9
Eleanna Kaffe, Romina Fiorotto, Francesca Pellegrino, Valeria Mariotti, Mariangela Amenduni, Massimiliano Cadamuro, Luca Fabris, Mario Strazzabosco, Carlo Spirli
Congenital Hepatic Fibrosis (CHF), a genetic disease caused by mutations in the PKHD1 gene, encoding for the protein fibrocystin (FPC), is characterized by biliary dysgenesis, progressive portal fibrosis, and by a PKA-mediated activating phosphorylation of β-Catenin at Ser675. Biliary structures of Pkhd1del4/del4 mice, a mouse model of CHF, secrete CXCL10 a chemokine able to recruit macrophages. The aim of this study is to clarify whether CXCL10 plays a pathogenetic role in disease progression in CHF/CD and to understand the mechanisms leading to increased CXCL10 secretion...
November 15, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29055424/a-new-epitope-tagged-pkhd1-allele-sheds-light-on-fibrocystin%C3%A2-signaling
#10
Wendy A Lea, Christopher J Ward
In this issue of Kidney International, Outeda et al. present a new epitope-tagged allele of murine Pkhd1 that allows the monitoring of functional fibrocystin in vivo from the extreme C-terminus of the molecule. This work also shows that the removal of two-thirds of the intracellular tail of fibrocystin does not result in cystogenesis in either the liver or kidney, with major implications for our understanding of Pkhd1 function and polycystic kidney disease in general.
November 2017: Kidney International
https://www.readbyqxmd.com/read/28933340/renal-histology-and-mri-findings-in-a-37-year-old-japanese-patient-with-autosomal-recessive-polycystic-kidney-disease%C3%A2
#11
Yusuke Ito, Akinari Sekine, Daisuke Takada, Junko Yabuuchi, Yuta Kogure, Toshiharu Ueno, Keiichi Sumida, Masayuki Yamanouchi, Noriko Hayami, Tatsuya Suwabe, Junichi Hoshino, Naoki Sawa, Kenmei Takaichi, Keiichi Kinowaki, Takeshi Fujii, Kenichi Ohashi, Hiroaki Kikuchi, Shintaro Mandai, Motoko Chiga, Takayasu Mori, Eisei Sohara, Shinichi Uchida, Yoshifumi Ubara
A 37-year-old Japanese man with a serum creatinine level of 2.5 mg/dL and hepatomegaly was admitted to our hospital for investigation of renal failure. Magnetic resonance imaging (MRI) showed hepatomegaly with small cystic lesions that had high signal intensity on T2-weighted images. There was no splenomegaly, and the kidneys were nearly normal in size with a few small cystic lesions. Renal biopsy revealed that interstitial fibrosis and tubular atrophy affected 60% of the cortex. There was cystic tubular dilation, mainly affecting the distal loop of Henle and distal tubules, since immunohistochemical staining of the dilated tubules was positive for cytokeratin 7 and Tamm-Horsfall protein but was negative for aquaporin 3 and CD10...
November 2017: Clinical Nephrology
https://www.readbyqxmd.com/read/28814334/abernethy-malformation-associated-with-caroli-s-syndrome-in-a-patient-with-a-pkhd1-mutation-a-case-report
#12
Xiao-Xiao Mi, Xiao-Guang Li, Zi-Rong Wang, Ling Lin, Chun-Hai Xu, Jun-Ping Shi
BACKGROUND: Abernethy malformation is a rare congenital anomaly characterised by the partial or complete absence of the portal vein and the subsequent development of an extrahepatic portosystemic shunt. Caroli's disease is a rare congenital condition characterised by non-obstructive saccular intrahepatic bile duct dilation. Caroli's disease combined with congenital hepatic fibrosis and/or renal cystic disease is referred to - Caroli's syndrome. The combination of Abernethy malformation and Caroli's syndrome has not been reported previously...
August 16, 2017: Diagnostic Pathology
https://www.readbyqxmd.com/read/28798345/nedd4-family-e3-ligase-dysfunction-due-to-pkhd1-pkhd1-defects-suggests-a-mechanistic-model-for-arpkd-pathobiology
#13
Jun-Ya Kaimori, Cheng-Chao Lin, Patricia Outeda, Miguel A Garcia-Gonzalez, Luis F Menezes, Erum A Hartung, Ao Li, Guanqing Wu, Hideaki Fujita, Yasunori Sato, Yasuni Nakanuma, Satoko Yamamoto, Naotsugu Ichimaru, Shiro Takahara, Yoshitaka Isaka, Terry Watnick, Luiz F Onuchic, Lisa M Guay-Woodford, Gregory G Germino
Autosomal recessive polycystic kidney disease (ARPKD) is an important childhood nephropathy, occurring 1 in 20,000 live births. The major clinical phenotypes are expressed in the kidney with dilatation of the collecting ducts, systemic hypertension, and progressive renal insufficiency, and in the liver with biliary dysgenesis, portal tract fibrosis, and portal hypertension. The systemic hypertension has been attributed to enhanced distal sodium reabsorption in the kidney, the structural defects have been ascribed to altered cellular morphology, and fibrosis to increased TGF-β signaling in the kidney and biliary tract, respectively...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28729032/a-novel-model-of-autosomal-recessive-polycystic-kidney-questions-the-role-of-the-fibrocystin-c-terminus-in-disease-mechanism
#14
Patricia Outeda, Luis Menezes, Erum A Hartung, Stacey Bridges, Fang Zhou, Xianjun Zhu, Hangxue Xu, Qiong Huang, Qin Yao, Feng Qian, Gregory G Germino, Terry Watnick
Autosomal recessive polycystic kidney disease (OMIM 263200) is a serious condition of the kidney and liver caused by mutations in a single gene, PKHD1. This gene encodes fibrocystin/polyductin (FPC, PD1), a large protein shown by in vitro studies to undergo Notch-like processing. Its cytoplasmic tail, reported to include a ciliary targeting sequence, a nuclear localization signal, and a polycystin-2 binding domain, is thought to traffic to the nucleus after cleavage. We now report a novel mouse line with a triple HA-epitope "knocked-in" to the C-terminus along with lox P sites flanking exon 67, which encodes most of the C-terminus (Pkhd1(Flox67HA))...
November 2017: Kidney International
https://www.readbyqxmd.com/read/28709963/animal-models-of-biliary-injury-and-altered-bile-acid-metabolism
#15
REVIEW
Valeria Mariotti, Mario Strazzabosco, Luca Fabris, Diego F Calvisi
In the last 25years, a number of animal models, mainly rodents, have been generated with the goal to mimic cholestatic liver injuries and, thus, to provide in vivo tools to investigate the mechanisms of biliary repair and, eventually, to test the efficacy of innovative treatments. Despite fundamental limitations applying to these models, such as the distinct immune system and the different metabolism regulating liver homeostasis in rodents when compared to humans, multiple approaches, such as surgery (bile duct ligation), chemical-induced (3,5-diethoxycarbonyl-1,4-dihydrocollidine, DDC, α-naphthylisothiocyanate, ANIT), viral infections (Rhesus rotavirustype A, RRV-A), and genetic manipulation (Mdr2, Cftr, Pkd1, Pkd2, Prkcsh, Sec63, Pkhd1) have been developed...
April 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28578020/pathogenicity-analysis-of-novel-variations-in-chinese-han-patients-with-polycystic-kidney-disease
#16
Zishui Fang, Shiyan Xu, Yonghua Wang, Liwei Sun, Yi Feng, Yibin Guo, Hongyi Li, Weiying Jiang
OBJECTIVE: Locus and allellic heterogeneity in polycystic kidney disease (PKD) is a great challenge in precision diagnosis. We aim to establish comprehensive methods to distinguish the pathogenic mutations from the variations in PKD1, PKD2 and PKHD1 genes in a limited time and lay the foundation for precisely prenatal diagnosis, preimplantation genetic diagnosis and presymptom diagnosis of PKD. METHODS: Nested PCR combined with direct DNA sequencing were used to screen variations in PKD1, PKD2 and PKHD1 genes...
August 30, 2017: Gene
https://www.readbyqxmd.com/read/28545714/anticystogenic-activity-of-a-small-molecule-pak4-inhibitor-may-be-a-novel-treatment-for-autosomal-dominant-polycystic-kidney-disease
#17
Vicki J Hwang, Xia Zhou, Xiaonan Chen, Josephine Trott, Omran Abu Aboud, Kyuhwan Shim, Lai Kuan Dionne, Kenneth J Chmiel, William Senapedis, Erkan Baloglu, Moe R Mahjoub, Xiaogang Li, Robert H Weiss
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common hereditary renal disease with no currently available targeted therapies. Based on the established connection between β-catenin signaling and renal ciliopathies, and on data from our and other laboratories showing striking similarities of this disease and cancer, we evaluated the use of an orally bioavailable small molecule, KPT-9274 (a dual inhibitor of the protein kinase PAK4 and nicotinamide phosphoribosyl transferase), for treatment of ADPKD...
October 2017: Kidney International
https://www.readbyqxmd.com/read/28543567/tgr5-contributes-to-hepatic-cystogenesis-in-rodents-with-polycystic-liver-diseases-through-cyclic-adenosine-monophosphate-g%C3%AE-s-signaling
#18
Tatyana V Masyuk, Anatoliy I Masyuk, Maria Lorenzo Pisarello, Brynn N Howard, Bing Q Huang, Pui-Yuen Lee, Xavier Fung, Eduard Sergienko, Robert J Ardecky, Thomas D Y Chung, Anthony B Pinkerton, Nicholas F LaRusso
Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease...
October 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28530676/mutations-in-dzip1l-which-encodes-a-ciliary-transition-zone-protein-cause-autosomal-recessive-polycystic-kidney-disease
#19
Hao Lu, Maria C Rondón Galeano, Elisabeth Ott, Geraldine Kaeslin, P Jaya Kausalya, Carina Kramer, Nadina Ortiz-Brüchle, Nadescha Hilger, Vicki Metzis, Milan Hiersche, Shang Yew Tay, Robert Tunningley, Shubha Vij, Andrew D Courtney, Belinda Whittle, Elke Wühl, Udo Vester, Björn Hartleben, Steffen Neuber, Valeska Frank, Melissa H Little, Daniel Epting, Peter Papathanasiou, Andrew C Perkins, Graham D Wright, Walter Hunziker, Heon Yung Gee, Edgar A Otto, Klaus Zerres, Friedhelm Hildebrandt, Sudipto Roy, Carol Wicking, Carsten Bergmann
Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone...
July 2017: Nature Genetics
https://www.readbyqxmd.com/read/28522687/integrin-linked-kinase-signaling-promotes-cyst-growth-and-fibrosis-in-polycystic-kidney-disease
#20
Archana Raman, Gail A Reif, Yuqiao Dai, Aditi Khanna, Xiaogang Li, Lindsay Astleford, Stephen C Parnell, James P Calvet, Darren P Wallace
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by innumerous fluid-filled cysts and progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is markedly overexpressed by cyst epithelial cells. Periostin promotes cell proliferation, cyst growth, interstitial fibrosis, and the decline in renal function in PKD mice. Here, we investigated the regulation of these processes by the integrin-linked kinase (ILK), a scaffold protein that links the extracellular matrix to the actin cytoskeleton and is stimulated by periostin...
September 2017: Journal of the American Society of Nephrology: JASN
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