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Maria Toms, Thomas Burgoyne, Dhani Tracey-White, Rose Richardson, Adam M Dubis, Andrew R Webster, Clare Futter, Mariya Moosajee
Mutations in KCNJ13 are associated with two retinal disorders; Leber congenital amaurosis (LCA) and snowflake vitreoretinal degeneration (SVD). We examined the retina of kcnj13 mutant zebrafish (obelixtd15 , c.502T > C p.[Phe168Leu]) to provide new insights into the pathophysiology underlying these conditions. Detailed phenotyping of obelixtd15 fish revealed a late onset retinal degeneration at 12 months. Electron microscopy of the obelixtd15 retinal pigment epithelium (RPE) uncovered reduced phagosome clearance and increased mitochondrial number and size prior any signs of retinal degeneration...
March 7, 2019: Scientific Reports
Pawan K Shahi, Dalton Hermans, Divya Sinha, Simran Brar, Hannah Moulton, Sabrina Stulo, Katarzyna D Borys, Elizabeth Capowski, De-Ann M Pillers, David M Gamm, Bikash R Pattnaik
Pathogenic variants of the KCNJ13 gene are known to cause Leber congenital amaurosis (LCA16), an inherited pediatric blindness. KCNJ13 encodes the Kir7.1 subunit that acts as a tetrameric, inwardly rectifying potassium ion channel in the retinal pigment epithelium (RPE) to maintain ionic homeostasis and allow photoreceptors to encode visual information. We sought to determine whether genetic approaches might be effective in treating blindness arising from pathogenic variants in KCNJ13. We derived human induced pluripotent stem cell (hiPSC)-RPE cells from an individual carrying a homozygous c...
January 15, 2019: American Journal of Human Genetics
E J P Anderson, M Ghamari-Langroudi, I Cakir, M J Litt, Valerie Chen, Roman E Reggiardo, Glenn L Millhauser, R D Cone
Energy stores in fat tissue are determined in part by the activity of hypothalamic neurons expressing the melanocortin-4 receptor (MC4R). Even partial reduction in MC4R expression levels in mice, rats, or humans produces hyperphagia and morbid obesity. Thus, it is of great interest to understand the molecular basis of neuromodulation by the MC4R. The MC4R is a G protein-coupled receptor that signals efficiently through GαS , and this signaling pathway is essential for normal MC4R function in vivo. However, previous data from hypothalamic slice preparations indicated that activation of the MC4R depolarized neurons through G protein-independent regulation of the ion channel Kir7...
December 17, 2018: Journal of Neuroendocrinology
Mikus Abolins-Abols, Etienne Kornobis, Paolo Ribeca, Kazumasa Wakamatsu, Mark P Peterson, Ellen D Ketterson, Borja Milá
Colour plays a prominent role in species recognition; therefore, understanding the proximate basis of pigmentation can provide insight into reproductive isolation and speciation. Colour differences between taxa may be the result of regulatory differences or be caused by mutations in coding regions of the expressed genes. To investigate these two alternatives, we studied the pigment composition and the genetic basis of coloration in two divergent dark-eyed junco (Junco hyemalis) subspecies, the slate-coloured and Oregon juncos, which have evolved marked differences in plumage coloration since the Last Glacial Maximum...
September 25, 2018: Molecular Ecology
Guoxin Ying, Karsten Boldt, Marius Ueffing, Cecilia D Gerstner, Jeanne M Frederick, Wolfgang Baehr
RAB28, a member of the RAS oncogene family, is a ubiquitous, farnesylated, small GTPase of unknown function present in photoreceptors and the retinal pigmented epithelium (RPE). Nonsense mutations of the human RAB28 gene cause recessive cone-rod dystrophy 18 (CRD18), characterized by macular hyperpigmentation, progressive loss of visual acuity, RPE atrophy, and severely attenuated cone and rod electroretinography (ERG) responses. In an attempt to elucidate the disease-causing mechanism, we generated Rab28 -/- mice by deleting exon 3 and truncating RAB28 after exon 2...
November 9, 2018: Journal of Biological Chemistry
Wenguang Yin, Hyun-Taek Kim, ShengPeng Wang, Felix Gunawan, Lei Wang, Keishi Kishimoto, Hua Zhong, Dany Roman, Jens Preussner, Stefan Guenther, Viola Graef, Carmen Buettner, Beate Grohmann, Mario Looso, Mitsuru Morimoto, Graeme Mardon, Stefan Offermanns, Didier Y R Stainier
Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity...
July 19, 2018: Nature Communications
Dany Roman, Hua Zhong, Sergey Yaklichkin, Rui Chen, Graeme Mardon
The retina is the light sensing tissue of the eye which contains multiple layers of cells required for the detection and transmission of a visual signal. Loss of the light-sensing photoreceptors leads to defects in visual function and blindness. Previously, we found that mosaic deletion of Kcnj13, and subsequent loss of the potassium channel Kir7.1, in mice leads to photoreceptor degeneration and recapitulates the human retinal disease phenotype (Zhong et al., 2015). Kcnj13 expression in the retinal pigment epithelium (RPE) is essential for normal retinal electrophysiology, function, and survival...
November 2018: Experimental Eye Research
Dan Yi, Wenkai Liu, Yongqing Hou, Lei Wang, Di Zhao, Tao Wu, Binying Ding, Guoyao Wu
A useful animal model of intestinal injury is pivotal for studying its pathogenesis and developing nutritional interventions (e.g., amino acid supplementation). Here, we propose the use of indomethacin (IDMT) to induce intestinal inflammation in neonatal pigs. Fourteen-day-old piglets fed a milk replacer diet receive intraperitoneal administration of IDMT (5 mg/kg body weight) for 3 consecutive days. On day 4, blood and intestinal samples are obtained for physiological and biochemical analyses. IDMT increases blood DAO activity, I-FABP concentration, neutrophil and eosinophil numbers; intestinal MMP3 mRNA levels, MPO activity, and MDA concentration; but reduces the plasma concentration of citrulline (synthesized exclusively by enterocytes of the small intestine), intestinal GSH-Px activity, and mRNA levels for villin , I-FABP , TRPV6 , AQP10 , and KCNJ13 ...
June 1, 2018: Frontiers in Bioscience (Landmark Edition)
Isabel Cornejo, Sandra Villanueva, Johanna Burgos, Karen I López-Cayuqueo, Régine Chambrey, Francisca Julio-Kalajzić, Neudo Buelvas, María I Niemeyer, Dulce Figueiras-Fierro, Peter D Brown, Francisco V Sepúlveda, L P Cid
Kir7.1 encoded by the Kcnj13 gene in the mouse is an inwardly rectifying K+ channel present in epithelia where it shares membrane localization with the Na+ /K+ -pump. Further investigations of the localisation and function of Kir7.1 would benefit from the availability of a knockout mouse, but perinatal mortality attributed to cleft palate in the neonate has thwarted this research. To facilitate localisation studies we now use CRISPR/Cas9 technology to generate a knock-in mouse, the Kir7.1-HA that expresses the channel tagged with a haemagglutinin (HA) epitope...
2018: Frontiers in Physiology
Yang Lv, Xueni Li, Lin Zhang, Yutao Shi, Linxiao DU, Binying Ding, Yongqing Hou, Joshua Gong, Tao Wu
Enterotoxigenic Escherichia coli (ETEC) is primary pathogenic bacteria of piglet diarrhea, over two thirds of piglets diarrhea caused by ETEC are resulted from STa-producing ETEC strains. This experiment was conducted to construct the recombinant E. coli expressing STa and study the injury and mechanism of recombinant E. coli expressing STa on 7 days old piglets colon. Twenty-four 7 days old piglets were allotted to four treatments: control group, STa group (2 × 109 CFU E. coli LMG194-STa), LMG194 group (2 × 109 CFU E...
February 9, 2018: Journal of Veterinary Medical Science
Pawan K Shahi, Xinling Liu, Bryce Aul, Andrea Moyer, Akshita Pattnaik, Jerod Denton, De-Ann M Pillers, Bikash R Pattnaik
The KCNJ13 gene encodes the inwardly rectifying potassium channel, Kir7.1. Mutations in this gene cause childhood blindness, in which the a- and b-wave responses of electroretinogram (ERG) are abolished. The ERG a-wave is the light-induced hyperpolarization of retinal photoreceptors, and the b-wave is the depolarization of ON-bipolar cells. The Kir7.1 channel is localized to the apical aspects of retinal pigment epithelium (RPE) cells and contributes to a delayed c-wave response. We sought to understand why a defect in an RPE ion-channel result in abnormal electrophysiology at the level of the retinal neurons...
September 6, 2017: Scientific Reports
Anna Sophia Japp, Ludger Klein-Hitpass, Dorota Denkhaus, Torsten Pietsch
Atypical teratoid rhabdoid tumors (ATRT) are highly malignant brain tumors of early childhood that have been regarded as a homogenous entity characterized by inactivation of the SMARCB1/INI1 or SMARCA4/BRG1 genes as the only characteristic alteration. Recent studies suggest that similar to other embryonal tumors ATRT can also be divided into subgroups based on their mRNA or methylation profiles. Using microarray-based expression analysis of 12 patient ATRT specimens we demonstrated the existence of 2 subgroups of ATRT...
January 1, 2017: Journal of Neuropathology and Experimental Neurology
Sarah Perez-Roustit, Virginie Marquette, Béatrice Bocquet, Josseline Kaplan, Isabelle Perrault, Isabelle Meunier, Christian P Hamel
PURPOSE: To describe a patient with mutations in KCNJ13 presenting particular clinical features. METHODS: Standard ophthalmic examination, fundus autofluorescence, spectral domain optical coherence tomography, full-field electroretinography. The 3 exons of KCNJ13 were polymerase chain reaction amplified and Sanger sequenced. PATIENTS: A 31-year-old man with Leber congenital amaurosis. RESULTS: Patient had nystagmus since childhood, best-corrected visual acuity limited to 20/400 OD and 20/200 OS, and had cataracts extracted in both eyes...
July 2017: Retinal Cases & Brief Reports
Daniel R Swale, Haruto Kurata, Sujay V Kharade, Jonathan Sheehan, Rene Raphemot, Karl R Voigtritter, Eric E Figueroa, Jens Meiler, Anna L Blobaum, Craig W Lindsley, Corey R Hopkins, Jerod S Denton
The inward rectifier potassium (Kir) channel Kir7.1 (KCNJ13) has recently emerged as a key regulator of melanocortin signaling in the brain, electrolyte homeostasis in the eye, and uterine muscle contractility during pregnancy. The pharmacological tools available for exploring the physiology and therapeutic potential of Kir7.1 have been limited to relatively weak and nonselective small-molecule inhibitors. Here, we report the discovery in a fluorescence-based high-throughput screen of a novel Kir7.1 channel inhibitor, VU714...
July 20, 2016: ACS Chemical Neuroscience
Sandra Villanueva, Johanna Burgos, Karen I López-Cayuqueo, Ka-Man Venus Lai, David M Valenzuela, L Pablo Cid, Francisco V Sepúlveda
Kir7.1 is an inwardly rectifying K+ channel of the Kir superfamily encoded by the kcnj13 gene. Kir7.1 is present in epithelial tissues where it colocalizes with the Na+/K+-pump probably serving to recycle K+ taken up by the pump. Human mutations affecting Kir7.1 are associated with retinal degeneration diseases. We generated a mouse lacking Kir7.1 by ablation of the Kcnj13 gene. Homozygous mutant null mice die hours after birth and show cleft palate and moderate retardation in lung development. Kir7.1 is expressed in the epithelium covering the palatal processes at the time at which palate sealing takes place and our results suggest it might play an essential role in late palatogenesis...
2015: PloS One
Hua Zhong, Yiyun Chen, Yumei Li, Rui Chen, Graeme Mardon
No abstract text is available yet for this article.
2015: Scientific Reports
Bikash R Pattnaik, Pawan K Shahi, Meghan J Marino, Xinying Liu, Nathaniel York, Simran Brar, John Chiang, De-Ann M Pillers, Elias I Traboulsi
Mutations in the KCNJ13 gene that encodes the inwardly rectifying potassium channel Kir7.1 cause snowflake vitreoretinal degeneration (SVD) and leber congenital amaurosis (LCA). Kir7.1 controls the microenvironment between the photoreceptors and the retinal pigment epithelium (RPE) and also contributes to the function of other organs such as uterus and brain. Heterologous expressions of the mutant channel have suggested a dominant-negative loss of Kir7.1 function in SVD, but parallel studies in LCA16 have been lacking...
July 2015: Human Mutation
Hua Zhong, Yiyun Chen, Yumei Li, Rui Chen, Graeme Mardon
The era of genomics has demanded the development of more efficient and timesaving approaches to validate gene function in disease. Here, we utilized the CRISPR-Cas9 system to generate Kcnj13 mutant mice by zygote injection to verify the pathogenic role of human KCNJ13, mutations of which are thought to cause Leber congenital amaurosis (LCA), an early-onset form of blindness. We found that complete loss of Kcnj13 is likely postnatal lethal. Among surviving F0-generation mice examined, 80% show mosaic KCNJ13 expression in the retinal pigment epithelium (RPE)...
2015: Scientific Reports
Arif O Khan, Carsten Bergmann, Christine Neuhaus, Hanno J Bolz
PURPOSE: To document a distinct vitreo-retinal dystrophy with early-onset cataract as related to recessive KCNJ13 mutations. METHODS: A retrospective case series (two patients from two families) Results: A 12-year-old Saudi Arabian girl with nystagmus since birth was referred because of recent decreased vision. Parents were first cousins and a younger sister had been diagnosed with retinal dystrophy. Examination revealed total white cataract in the right eye. In the left eye, there were posterior cortical lenticular opacities and an unusual retina fundus dystrophic appearance notable for fibrosis over the optic disc and clumped pigmentation...
March 2015: Ophthalmic Genetics
Ferhat Ozturk, You Li, Xiujuan Zhu, Chittibabu Guda, Ali Nawshad
BACKGROUND: In humans, cleft palate (CP) accounts for one of the largest number of birth defects with a complex genetic and environmental etiology. TGFβ3 has been established as an important regulator of palatal fusion in mice and it has been shown that TGFβ3-null mice exhibit CP without any other major deformities. However, the genes that regulate cellular decisions and molecular mechanisms maintained by the TGFβ3 pathway throughout palatogenesis are predominantly unexplored. Our objective in this study was to analyze global transcriptome changes within the palate during different gestational ages within TGFβ3 knockout mice to identify TGFβ3-associated genes previously unknown to be associated with the development of cleft palate...
2013: BMC Genomics
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