Genetics and Genomics Commons^™

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum And Novel Clinical Observations In 241 Patients, Rachael C. Heath Jeffery, Jennifer A. Thompson, Johnny Lo, Enid S. Chelva, Sean Armstrong, Jose S. Pulido, Rebecca Procopio, Andrea L. Vincent, Lorenzo Bianco, Maurizio Battaglia Parodi, Lucia Ziccardi, Giulio Antonelli, Lucilla Barbano, João P. Marques, Sara Geada, Ana L. Carvalho, Wei C. Tang, Choi M. Chan, Camiel J. F. Boon, Jonathan Hensman, Ta-Ching Chen, Chien-Yu Lin, Pei-Lung Chen, Ajoy Vincent, Anupreet Tumber, Elise Heon, John R. Grigg, Robyn V. Jamieson, Elisa E. Cornish, Benjamin M. Nash, Shyamanga Borooah, Lauren N. Ayton, Alexis Ceecee Britten-Jones, Thomas L. Edwards, Jonathan B. Ruddle, Abhishek Sharma, Rowan G. Porter, Tina M. Lamey, Terri L. Mclaren, Samuel Mclenachan, Danial Roshandel, Fred K. Chen

Wills Eye Hospital Papers

PURPOSE: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene.

METHODS: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations.

RESULTS: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, …

A Rare Metastatic Mesenteric Malignant Pecoma With Tsc2 Mutation Treated With Palliative Surgical Resection And Nab-Sirolimus: A Case Report, Luke Meredith, Timothy Chao, Avinoam Nevler, Atrayee Basu Mallick, Rajan Singla, Peter Mccue, Wilbur Bowne, Wei Jiang, Md, Phd

Kimmel Cancer Center Faculty Papers

BACKGROUND: Malignant perivascular epithelioid cell tumors (PEComas) are exceedingly rare malignant mesenchymal neoplasms with characteristic morphological and immunohistochemical (IHC) patterns. However, some malignant PEComas are poorly differentiated with atypical histopathological features, making a definitive diagnosis difficult. PEComas are most commonly found in females and often show either TSC1 or TSC2 alterations, which result in the activation of the mTOR pathway, or TFE3 fusions. Given these molecular characteristics, mTOR inhibitors have recently been approved by the FDA in the treatment of malignant PEComas, particularly in those with TSC1/2 alterations. Therefore, molecular analyses may be helpful for both the diagnostic workup of …

Comparative Risks Of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease, Ellen S Regalado, Shaine A Morris, Alan C Braverman, Ellen M Hostetler, Julie De Backer, Ruosha Li, Reed E Pyeritz, Anji T Yetman, Elena Cervi, Sherene Shalhub, Richmond Jeremy, Scott Lemaire, Maral Ouzounian, Arturo Evangelista, Catherine Boileau, Guillaume Jondeau, Dianna M Milewicz

Journal Articles

BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes.

OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene.

METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, …

Determinants Of Virus Variation, Evolution, And Host Adaptation, Katherine Latourrette, Hernan Garcia-Ruiz

Nebraska Center for Virology: Faculty Publications

Virus evolution is the change in the genetic structure of a viral population over time and results in the emergence of new viral variants, strains, and species with novel biological properties, including adaptation to new hosts. There are host, vector, environmental, and viral factors that contribute to virus evolution. To achieve or fine tune compatibility and successfully establish infection, viruses adapt to a particular host species or to a group of species. However, some viruses are better able to adapt to diverse hosts, vectors, and environments. Viruses generate genetic diversity through mutation, reassortment, and recombination. Plant viruses are exposed to …

Genotype-Phenotype Study In Patients With Valosin-Containing Protein Mutations Associated With Multisystem Proteinopathy, Ebaa Al-Obeidi, Sejad Al-Tahan, Abhilasha Surampalli, Namita Goyal, Annabel K. Wang, Andreas Hermann, Molly Omizo, Charles D. Smith, Tahseen Mozaffar, Virginia Kimonis

Neurology Faculty Publications

Mutations in valosin‐containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in …

Zinc Transporters Ybtx And Znuabc Are Required For The Virulence Of Yersinia Pestis In Bubonic And Pneumonic Plague In Mice, Alexander G. Bobrov, Olga Kirillina, Marina Y. Fosso, Jacqueline D. Fetherston, M. Clarke Miller, Tiva T. Vancleave, Joseph A. Burlison, William K. Arnold, Matthew B. Lawrenz, Sylvie Garneau-Tsodikova, Robert D. Perry

Microbiology, Immunology, and Molecular Genetics Faculty Publications

A number of bacterial pathogens require the ZnuABC Zinc (Zn²⁺) transporter and/or a second Zn²⁺ transport system to overcome Zn²⁺ sequestration by mammalian hosts. Previously we have shown that in addition to ZnuABC, Yersinia pestis possesses a second Zn²⁺ transporter that involves components of the yersiniabactin (Ybt), siderophore-dependent iron transport system. Synthesis of the Ybt siderophore and YbtX, a member of the major facilitator superfamily, are both critical components of the second Zn²⁺ transport system. Here we demonstrate that a ybtX znu double mutant is essentially avirulent in mouse models of bubonic and pneumonic …

High Resolution Time-Course Mapping Of Early Transcriptomic, Molecular And Cellular Phenotypes In Huntington's Disease Cag Knock-In Mice Across Multiple Genetic Backgrounds., Seth A Ament, Jocelynn R Pearl, Andrea Grindeland, Jason St Claire, John C Earls, Marina Kovalenko, Tammy Gillis, Jayalakshmi Mysore, James F Gusella, Jong-Min Lee, Seung Kwak, David Howland, Min Young Lee, David Baxter, Kelsey Scherler, Kai Wang, Donald Geman, Jeffrey B Carroll, Marcy E Macdonald, George Carlson, Vanessa C Wheeler, Nathan D Price, Leroy Hood

Articles, Abstracts, and Reports

Huntington's disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, …

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

University Scholar Projects

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed, …

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

Honors Scholar Theses

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed, …

Accumulation Of Rhodopsin In Late Endosomes Triggers Photoreceptor Cell Degeneration, Yashodhan Chinchore, Amitavo Mitra, Patrick J. Dolph, Norbert Perrimon

Dartmouth Scholarship

Progressive retinal degeneration is the underlying feature of many human retinal dystrophies. Previous work using Drosophila as a model system and analysis of specific mutations in human rhodopsin have uncovered a connection between rhodopsin endocytosis and retinal degeneration. In these mutants, rhodopsin and its regulatory protein arrestin form stable complexes, and endocytosis of these complexes causes photoreceptor cell death. In this study we show that the internalized rhodopsin is not degraded in the lysosome but instead accumulates in the late endosomes. Using mutants that are defective in late endosome to lysosome trafficking, we were able to show that rhodopsin accumulates …