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Amy Christine Engevik, James R Goldenring
Epithelial cells lining the gastrointestinal tract require distinct apical and basolateral domains to function properly. Trafficking and insertion of enzymes and transporters into the apical brush border of intestinal epithelial cells is essential for effective digestion and absorption of nutrients. Specific critical ion transporters are delivered to the apical brush border to facilitate fluid and electrolyte uptake. Maintenance of these apical transporters requires both targeted delivery and regulated membrane recycling...
March 6, 2017: Cold Spring Harbor Perspectives in Biology
Yi-Ling Qiu, Jing-Yu Gong, Jia-Yan Feng, Ren-Xue Wang, Jun Han, Teng Liu, Yi Lu, Li-Ting Li, Mei-Hong Zhang, Jonathan A Sheps, Neng-Li Wang, Yan-Yan Yan, Jia-Qi Li, Lian Chen, Christoph H Borchers, Bence Sipos, A S Knisely, Victor Ling, Qing-He Xing, Jian-She Wang
Hereditary cholestasis in childhood and infancy with normal serum gamma-glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation...
May 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Man Mao, Li Guo, Zhanhui Zhang, Bin Wang, Shanhua Huang, Yuanzong Song, Fengping Chen, Wangrong Wen
OBJECTIVE: To explore the clinical features and mutations of MYO5B gene in a family affected with microvillus inclusion disease. METHODS: Clinical data of an infant affected with microvillus inclusion disease was collected. Genomic DNA was extracted from peripheral blood samples from the patient and her parents. PCR amplification and Sanger sequencing were performed to analyze all the exons and their flanking sequences of the MYO5B gene. RESULTS: The patient presented with complicated manifestations including respiratory distress syndrome, dehydration, acidosis, bowel dilatation, liver and kidney dysfunction, and severe and intractable diarrhea...
December 10, 2016: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Jing Dong, Annah Wyss, Jingyun Yang, T Ryan Price, Aude Nicolas, Michael Nalls, Greg Tranah, Nora Franceschini, Zongli Xu, Claudia Schulte, Alvaro Alonso, Steven R Cummings, Myriam Fornage, Dmitri Zaykin, Leping Li, Xuemei Huang, Stephen Kritchevsky, Yongmei Liu, Thomas Gasser, Robert S Wilson, Philip L De Jager, Andrew B Singleton, Jayant M Pinto, Tamara Harris, Thomas H Mosley, David A Bennett, Stephanie London, Lei Yu, Honglei Chen
The human sense of smell decreases with age, and a poor sense of smell are among the most important prodromal symptoms of several neurodegenerative diseases. Recent evidence further suggests a racial difference in the sense of smell among U.S. older adults. However, no genome-wide association study (GWAS) on the sense of smell has been conducted in African-Americans (AAs). We performed the first genome-wide meta-analysis of the sense of smell among 1979 AAs and 6582 European-Americans (EAs) from three U.S. aging cohorts...
November 23, 2016: Molecular Neurobiology
Emmanuel Gonzales, Sarah A Taylor, Anne Davit-Spraul, Alice Thébaut, Nadège Thomassin, Catherine Guettier, Peter F Whitington, Emmanuel Jacquemin
Some patients with microvillus inclusion disease due to myosin 5B (MYO5B) mutations may develop cholestasis characterized by a progressive familial intrahepatic cholestasis-like phenotype with normal serum gamma-glutamyl transferase activity. So far MYO5B deficiency has not been reported in patients with such a cholestasis phenotype in the absence of intestinal disease. Using a new-generation sequencing approach, we identified MYO5B mutations in five patients with progressive familial intrahepatic cholestasis-like phenotype with normal serum gamma-glutamyl transferase activity without intestinal disease...
January 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Amit K Mitra, Holly A F Stessman, Robert J Schaefer, Wen Wang, Chad L Myers, Brian G Van Ness, Soraya Beiraghi
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital birth defects. NSCL/P is a complex multifactorial disease caused by interactions between multiple environmental and genetic factors. However, the causal single nucleotide polymorphism (SNP) signature profile underlying the risk of familial NSCL/P still remains unknown. We previously reported a 5.7-Mb genomic region on chromosome 18q21.1 locus that potentially contributes to autosomal dominant, low-penetrance inheritance of NSCL/P...
2016: Frontiers in Genetics
Dmitri V Kravtsov, Md Kaimul Ahsan, Vandana Kumari, Sven C D van Ijzendoorn, Miguel Reyes-Mugica, Anoop Kumar, Tarunmeet Gujral, Pradeep K Dudeja, Nadia A Ameen
Loss of function mutations in the actin motor myosin Vb (Myo5b) lead to microvillus inclusion disease (MVID) and death in newborns and children. MVID results in secretory diarrhea, brush border (BB) defects, villus atrophy, and microvillus inclusions (MVIs) in enterocytes. How loss of Myo5b results in increased stool loss of chloride (Cl(-)) and sodium (Na(+)) is unknown. The present study used Myo5b loss-of-function human MVID intestine, polarized intestinal cell models of secretory crypt (T84) and villus resembling (CaCo2BBe, C2BBe) enterocytes lacking Myo5b in conjunction with immunofluorescence confocal stimulated emission depletion (gSTED) imaging, immunohistochemical staining, transmission electron microscopy, shRNA silencing, immunoblots, and electrophysiological approaches to examine the distribution, expression, and function of the major BB ion transporters NHE3 (Na(+)), CFTR (Cl(-)), and SLC26A3 (DRA) (Cl(-)/HCO3 (-)) that control intestinal fluid transport...
July 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Victoria G Weis, Byron C Knowles, Eunyoung Choi, Anna E Goldstein, Janice A Williams, Elizabeth H Manning, Joseph T Roland, Lynne A Lapierre, James R Goldenring
BACKGROUND AND AIMS: Inactivating mutations in MYO5B cause severe neonatal diarrhea in Microvillus Inclusion Disease. Loss of active MYO5B causes the formation of pathognomonic inclusions and aberrations in brush border enzymes. METHODS: We developed three mouse models of germline, constitutively intestinal targeted and inducible intestinal targeted deletion of MYO5B. The mice were evaluated for enterocyte cellular morphology. RESULTS: Germline MYO5B KO mice showed early diarrhea and failure to thrive with evident microvillus inclusions and loss of apical transporters in the duodenum...
February 1, 2016: Cellular and Molecular Gastroenterology and Hepatology
Lin-Lin Yao, Mei Shen, Zekuan Lu, Mitsuo Ikebe, Xiang-dong Li
Vertebrates have three isoforms of class V myosin (Myo5), Myo5a, Myo5b, and Myo5c, which are involved in transport of multiple cargoes. It is well established that the motor functions of Myo5a and Myo5b are regulated by a tail inhibition mechanism. Here we found that the motor function of Myo5c was also inhibited by its globular tail domain (GTD), and this inhibition was abolished by high Ca(2+), indicating that the tail inhibition mechanism is conserved in vertebrate Myo5. Interestingly, we found that Myo5a-GTD and Myo5c-GTD were not interchangeable in terms of inhibition of motor function, indicating isoform-specific interactions between the GTD and the head of Myo5...
April 8, 2016: Journal of Biological Chemistry
Georg F Vogel, Michael W Hess, Kristian Pfaller, Lukas A Huber, Andreas R Janecke, Thomas Müller
Microvillus inclusion disease (MVID) is characterised by onset of intractable life-threatening watery diarrhoea during infancy. Transmission electron microscopy demonstrates shortening or absence of apical microvilli, pathognomonic microvillus inclusions in mature enterocytes and subapical accumulation of periodic acid-Schiff-positive granules or vesicles confirming diagnosis. Mutations in MYO5B have been found to cause MVID. In two patients with MVID, whole-exome sequencing of DNA revealed homozygous truncating mutations in STX3...
December 2016: Molecular and Cellular Pediatrics
Annica Wilzén, Anna Rehammar, Andreas Muth, Ola Nilsson, Tajana Tešan Tomić, Bo Wängberg, Erik Kristiansson, Frida Abel
One out of ten patients with pheochromocytoma (PCC) and paraganglioma (PGL) develop malignant disease. Today there are no reliable pathological methods to predict malignancy at the time of diagnosis. Tumors harboring mutations in the succinate dehydrogenase subunit B (SDHB) gene often metastasize but the sequential genetic events resulting in malignant progression are not fully understood. The aim of this study was to identify somatic mutations that contribute to the malignant transformation of PCC/PGL. We performed pair-wise (tumor-normal) whole-exome sequencing to analyze the somatic mutational landscape in five malignant and four benign primary PCC/sympathetic PGL (sPGL), including two biological replicates from each specimen...
May 1, 2016: International Journal of Cancer. Journal International du Cancer
Georg F Vogel, Katharina M C Klee, Andreas R Janecke, Thomas Müller, Michael W Hess, Lukas A Huber
Mutations in the motor protein Myosin Vb (Myo5B) or the soluble NSF attachment protein receptor Syntaxin 3 (Stx3) disturb epithelial polarity and cause microvillus inclusion disease (MVID), a lethal hereditary enteropathy affecting neonates. To understand the molecular mechanism of Myo5B and Stx3 interplay, we used genome editing to introduce a defined Myo5B patient mutation in a human epithelial cell line. Our results demonstrate a selective role of Myo5B and Stx3 for apical cargo exocytosis in polarized epithelial cells...
November 9, 2015: Journal of Cell Biology
Grégoire Michaux, Dominique Massey-Harroche, Ophélie Nicolle, Marion Rabant, Nicole Brousse, Olivier Goulet, André Le Bivic, Frank M Ruemmele
BACKGROUND INFORMATION: Microvillus inclusion disease (MVID) is a genetic disorder affecting intestinal absorption. It is caused by mutations in MYO5B or syntaxin 3 (STX3) affecting apical membrane trafficking. Morphologically, MVID is characterised by a depletion of apical microvilli and the formation of microvillus inclusions inside the cells, suggesting a loss of polarity. To investigate this hypothesis, we examined the location of essential apical polarity determinants in five MVID patients...
January 2016: Biology of the Cell
Younhee Ko, CheolHo Lee, Myeong Hee Moon, Geu-Ru Hong, Chong-Kun Cheon, Jin-Sung Lee
Fabry disease (FD) is a rare X-linked recessive glycosphingolipid-storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Intravenous enzyme replacement therapy (ERT) has been used to supplement deficient enzyme activity in patients with FD. Despite its clinical effect and manifestations, clear criteria for the clinical effectiveness and cost-effectiveness of ERT have not been well established. In this study, we investigated the pharmacodynamic actions and short-term effects of ERT in patients with FD through direct molecular profiling from blood samples of patients before and after ERT...
February 2016: Journal of Human Genetics
Sabine Charron, François Roubertie, David Benoist, Virginie Dubes, Stephen H Gilbert, Marion Constantin, Delphine Vieillot, Delphine Elbes, Bruno Quesson, Pierre Bordachar, Michel Haissaguerre, Olivier Bernus, Jean-Benoit Thambo, Caroline Rooryck
Surgical repair of Tetralogy of Fallot (TOF) is highly successful but may be complicated in adulthood by arrhythmias, sudden death, and right ventricular or biventricular dysfunction. To better understand the molecular and cellular mechanisms of these delayed cardiac events, a chronic animal model of postoperative TOF was studied using microarrays to perform cardiac transcriptomic studies. The experimental study included 12 piglets (7 rTOF and 5 controls) that underwent surgery at age 2 months and were further studied after 23 (+/- 1) weeks of postoperative recovery...
2015: PloS One
W Z Wang, T Li, L J Shi, X R Yan, Y L Pan, X S Wu
The molecular mechanism underlying muscle development in rabbits is not well-understood. In the current study, differentially-expressed genes were scanned using an expression profile chip in New Zealand white rabbits (introduced breed) and Fujian yellow rabbits (local breed), and some of the genes were tested using reverse transcription-polymerase chain reaction. The amplification results were consistent with the microarray data. Fourteen and 13 genes involved in muscle development were identified in the dorsal longissimus and leg muscles, respectively...
2015: Genetics and Molecular Research: GMR
Fernando Cartón-García, Arend W Overeem, Rocio Nieto, Sarah Bazzocco, Higinio Dopeso, Irati Macaya, Josipa Bilic, Stefania Landolfi, Javier Hernandez-Losa, Simo Schwartz, Santiago Ramon y Cajal, Sven C D van Ijzendoorn, Diego Arango
Inherited MYO5B mutations have recently been associated with microvillus inclusion disease (MVID), an autosomal recessive syndrome characterized by intractable, life-threatening, watery diarrhea appearing shortly after birth. Characterization of the molecular mechanisms underlying this disease and development of novel therapeutic approaches is hampered by the lack of animal models. In this study we describe the phenotype of a novel mouse model with targeted inactivation of Myo5b. Myo5b knockout mice show perinatal mortality, diarrhea and the characteristic mislocalization of apical and basolateral plasma membrane markers in enterocytes...
2015: Scientific Reports
B Fernández Caamaño, M J Quiles Blanco, L Fernández Tomé, E Burgos Lizáldez, J Sarría Osés, M Molina Arias, G Prieto Bozano
INTRODUCTION: Microvillous inclusion disease is a rare autosomal recessive condition, characterized by severe secretory diarrhea that produces a permanent intestinal failure and dependency on parenteral nutrition. It usually begins in the neonatal period, and the only treatment at present is intestinal transplantation. PATIENTS AND METHODS: A retrospective review was conducted on 6 patients (three males and three females) diagnosed with microvillous inclusion disease between 1998 and 2013...
September 2015: Anales de Pediatría: Publicación Oficial de la Asociación Española de Pediatría (A.E.P.)
Dmitri Kravtsov, Anastasia Mashukova, Radia Forteza, Maria M Rodriguez, Nadia A Ameen, Pedro J Salas
Microvillus inclusion disease (MVID) is an autosomal recessive condition resulting in intractable secretory diarrhea in newborns due to loss-of-function mutations in myosin Vb (Myo5b). Previous work suggested that the apical recycling endosomal (ARE) compartment is the primary location for phosphoinositide-dependent protein kinase 1 (PDK1) signaling. Because the ARE is disrupted in MVID, we tested the hypothesis that polarized signaling is affected by Myo5b dysfunction. Subcellular distribution of PDK1 was analyzed in human enterocytes from MVID/control patients by immunocytochemistry...
November 15, 2014: American Journal of Physiology. Gastrointestinal and Liver Physiology
Cornelia Thoeni, Ernest Cutz
MVID, first reported in 1972 as a familial enteropathy is a congenital disorder of intestinal mucosa characterized by villous atrophy with marked abnormalities of enterocytes which on electron microscopy (EM) show loss of apical microvilli, intracytoplasmic microvillous inclusions as well as vesicular inclusion bodies and subapical secretory-like granules. The clinical manifestations include severe malabsorption and intractable watery diarrhea starting at birth (classical MVID) or at few days or weeks of age (variant MVID)...
October 2014: Pathology
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