Medicine and Health Sciences Commons^™

Alport Syndrome And Alport Kidney Diseases - Elucidating The Disease Spectrum, Pongpratch Puapatanakul, Jeffrey H. Miner

2020-Current year OA Pubs

PURPOSE OF REVIEW: With the latest classification, variants in three collagen IV genes, COL4A3 , COL4A4 , and COL4A5 , represent the most prevalent genetic kidney disease in humans, exhibiting diverse, complex, and inconsistent clinical manifestations. This review breaks down the disease spectrum and genotype-phenotype correlations of kidney diseases linked to genetic variants in these genes and distinguishes "classic" Alport syndrome (AS) from the less severe nonsyndromic genetically related nephropathies that we suggest be called "Alport kidney diseases".

RECENT FINDINGS: Several research studies have focused on the genotype-phenotype correlation under the latest classification scheme of AS. The historic diagnoses of …

Spatial Mapping Of Hematopoietic Clones In Human Bone Marrow, Andrew L Young, Hannah C Davis, Maggie J Cox, Tyler M Parsons, Samantha C Burkart, Diane E Bender, Lulu Sun, Stephen T Oh, Grant A Challen

2020-Current year OA Pubs

UNLABELLED: Clonal hematopoiesis (CH) is the expansion of somatically mutated cells in the hematopoietic compartment of individuals without hematopoietic dysfunction. Large CH clones (i.e., >2% variant allele fraction) predispose to hematologic malignancy, but CH is detected at lower levels in nearly all middle-aged individuals. Prior work has extensively characterized CH in peripheral blood, but the spatial distribution of hematopoietic clones in human bone marrow is largely undescribed. To understand CH at this level, we developed a method for spatially aware somatic mutation profiling and characterized the bone marrow of a patient with polycythemia vera. We identified the complex clonal distribution …

Disordered Clock Protein Interactions And Charge Blocks Turn An Hourglass Into A Persistent Circadian Oscillator, Meaghan S Jankowski, Daniel Griffith, Divya G Shastry, Jacqueline F Pelham, Garrett M Ginell, Joshua Thomas, Pankaj Karande, Alex S Holehouse, Jennifer M Hurley

2020-Current year OA Pubs

Organismal physiology is widely regulated by the molecular circadian clock, a feedback loop composed of protein complexes whose members are enriched in intrinsically disordered regions. These regions can mediate protein-protein interactions via SLiMs, but the contribution of these disordered regions to clock protein interactions had not been elucidated. To determine the functionality of these disordered regions, we applied a synthetic peptide microarray approach to the disordered clock protein FRQ in Neurospora crassa. We identified residues required for FRQ's interaction with its partner protein FRH, the mutation of which demonstrated FRH is necessary for persistent clock oscillations but not repression of …

A Protective Role For Type I Interferon Signaling Following Infection With Mycobacterium Tuberculosis Carrying The Rifampicin Drug Resistance-Conferring Rpob Mutation H445y, Suhas Bobba, Kuldeep S. Chauhan, Sadia Akter, Shibali Das, Ekansh Mittal, Barun Mathema, Jennifer A. Philips, Shabaana A. Khader

2020-Current year OA Pubs

Interleukin-1 (IL-1) signaling is essential for controlling virulent Mycobacterium tuberculosis (Mtb) infection since antagonism of this pathway leads to exacerbated pathology and increased susceptibility. In contrast, the triggering of type I interferon (IFN) signaling is associated with the progression of tuberculosis (TB) disease and linked with negative regulation of IL-1 signaling. However, mice lacking IL-1 signaling can control Mtb infection if infected with an Mtb strain carrying the rifampin-resistance conferring mutation H445Y in its RNA polymerase β subunit (rpoB-H445Y Mtb). The mechanisms that govern protection in the absence of IL-1 signaling during rpoB-H445Y Mtb infection are unknown. In this study, …

Arch: Improving The Performance Of Clonal Hematopoiesis Variant Calling And Interpretation, Irenaeus C C Chan, Alex Panchot, Evelyn Schmidt, Brian J Wiley, Jie Liu, Kimberly Turner, Duc Tran, J Scott Beeler, Armel Landry Batchi-Bouyou, Daniel C Link, Kelly L Bolton, Et Al.

2020-Current year OA Pubs

MOTIVATION: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. …

Inducing Vulnerability To Inha Inhibition Restores Isoniazid Susceptibility In Drug-Resistant Mycobacterium Tuberculosis, Gregory A Harrison, Erin R Wang, Kevin Cho, Yassin Mreyoud, Souvik Sarkar, Fredrik Almqvist, Gary J Patti, Christina L Stallings

2020-Current year OA Pubs

Of the approximately 10 million cases of

Gene Dosage Of Independent Dynein Arm Motor Preassembly Factors Influences Cilia Assembly In Chlamydomonas Reinhardtii, Gervette M. Penny, Susan K. Dutcher

2020-Current year OA Pubs

Motile cilia assembly utilizes over 800 structural and cytoplasmic proteins. Variants in approximately 58 genes cause primary ciliary dyskinesia (PCD) in humans, including the dynein arm (pre)assembly factor (DNAAF) gene DNAAF4. In humans, outer dynein arms (ODAs) and inner dynein arms (IDAs) fail to assemble motile cilia when DNAAF4 function is disrupted. In Chlamydomonas reinhardtii, a ciliated unicellular alga, the DNAAF4 ortholog is called PF23. The pf23-1 mutant assembles short cilia and lacks IDAs, but partially retains ODAs. The cilia of a new null allele (pf23-4) completely lack ODAs and IDAs and are even shorter than cilia from pf23-1. In …

Arid2 Mutations May Relay A Distinct Subset Of Cutaneous Melanoma Patients With Different Outcomes, Favour A Akinjiyan, George Nassief, Jordan Phillipps, Tolulope Adeyelu, Andrew Elliott, Farah Abdulla, Alice Y Zhou, George Souroullas, Kevin B Kim, Ari Vanderwalde, Soo J Park, George Ansstas

2020-Current year OA Pubs

ARID genes encode subunits of SWI/SNF chromatin remodeling complexes and are frequently mutated in human cancers. We investigated the correlation between ARID mutations, molecular features, and clinical outcomes in melanoma patients. Cutaneous melanoma samples (n = 1577) were analyzed by next-generation sequencing. Samples were stratified by pathogenic/likely pathogenic mutation in ARID genes (ARID1A/2/1B/5B). PD-L1 expression was assessed using IHC (SP142; positive (+): ≥ 1%). Tumor mutation burden (TMB)-high was defined as ≥ 10 mutations/Mb. Transcriptomic signatures predictive of response to immune checkpoint inhibitors-interferon gamma and T-cell inflamed score were calculated. Real-world overall survival (OS) information was obtained from insurance claims …

Genomemuster Mouse Genetic Variation Service Enables Multitrait, Multipopulation Data Integration And Analysis, Robyn L Ball, Alexander S Hatoum, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait-variant associations across populations, but these analyses are hampered by the sparsity of genotypes available. Moreover, the data are …

Rapid And Accurate Remethylation Of Dna In Dnmt3a- Deficient Hematopoietic Cells With Restoration Of Dnmt3a Activity, Yang Li, Haley J Abel, Michelle Cai, Taylor A Lavalle, Tiankai Yin, Nichole M Helton, Amanda M Smith, Christopher A Miller, Timothy J Ley

2020-Current year OA Pubs

Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency of

A Comparative Biochemical And Pathological Evaluation Of Brain Samples From Knock-In Murine Models Of Gaucher Disease, Makaila L Furderer, Bahafta Berhe, Tiffany C Chen, Stephen Wincovitch, Xuntian Jiang, Nahid Tayebi, Ellen Sidransky, Tae-Un Han

2020-Current year OA Pubs

Gaucher disease (GD) is a lysosomal storage disorder stemming from biallelic mutations in

Stem Cell Modeling Of Nervous System Tumors, Frank B Furnari, Corina Anastasaki, Shan Bian, Howard A Fine, Tomoyuki Koga, Lu Q Le, Fausto J Rodriguez, David H Gutmann

2020-Current year OA Pubs

Nervous system tumors, particularly brain tumors, represent the most common tumors in children and one of the most lethal tumors in adults. Despite decades of research, there are few effective therapies for these cancers. Although human nervous system tumor cells and genetically engineered mouse models have served as excellent platforms for drug discovery and preclinical testing, they have limitations with respect to accurately recapitulating important aspects of the pathobiology of spontaneously arising human tumors. For this reason, attention has turned to the deployment of human stem cell engineering involving human embryonic or induced pluripotent stem cells, in which genetic alterations …

Multiomic Profiling Reveals Metabolic Alterations Mediating Aberrant Platelet Activity And Inflammation In Myeloproliferative Neoplasms, Fan He, Angelo Ba Laranjeira, Tim Kong, Shuyang Lin, Katrina J. Ashworth, Alice Liu, Nina M. Lasky, Daniel Ac Fisher, Maggie J. Cox, Mary C. Fulbright, Lilian Antunes-Heck, Layow Yu, Molly Brakhane, Bei Gao, Stephen M. Sykes, Angelo D'Alessandro, Jorge Di Paola, Stephen T. Oh

2020-Current year OA Pubs

Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single-cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR, and oxidative phosphorylation in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid cycle, but lower α-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and …

Human Pluripotent Stem Cell Modeling Of Alveolar Type 2 Cell Dysfunction Caused By Abca3 Mutations, Yuliang L Sun, Erin E Hennessey, Hillary Heins, Ping Yang, Carlos Villacorta-Martin, Julian Kwan, Krithi Gopalan, Marianne James, Andrew Emili, F. Sessions Cole, Jennifer A. Wambach, Darrell N. Kotton

2020-Current year OA Pubs

Mutations in ATP-binding cassette A3 (ABCA3), a phospholipid transporter critical for surfactant homeostasis in pulmonary alveolar type II epithelial cells (AEC2s), are the most common genetic causes of childhood interstitial lung disease (chILD). Treatments for patients with pathological variants of ABCA3 mutations are limited, in part due to a lack of understanding of disease pathogenesis resulting from an inability to access primary AEC2s from affected children. Here, we report the generation of AEC2s from affected patient induced pluripotent stem cells (iPSCs) carrying homozygous versions of multiple ABCA3 mutations. We generated syngeneic CRISPR/Cas9 gene-corrected and uncorrected iPSCs and ABCA3-mutant knockin ABCA3:GFP …

Heterozygous Mutations In The C-Terminal Domain Of Copa Underlie A Complex Autoinflammatory Syndrome, Selket Delafontaine, Tarin M. Bigley, Megan A. Cooper, Et Al.

2020-Current year OA Pubs

Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular …

Cathepsin C Role In Inflammatory Gastroenterological, Renal, Rheumatic, And Pulmonary Disorders, Ali A Aghdassi, Christine Pham, Lukas Zierke, Vincent Mariaule, Brice Korkmaz, Moez Rhimi

2020-Current year OA Pubs

Cathepsin C (CatC, syn. Dipeptidyl peptidase I) is a lysosomal cysteine proteinase expressed in several tissues including inflammatory cells. This enzyme is important for maintaining multiple cellular functions and for processing immune cell-derived proteases. While mutations in the CatC gene were reported in Papillon-Lefèvre syndrome, a rare autosomal recessive disorder featuring hyperkeratosis and periodontitis, evidence from clinical and preclinical studies points toward pro-inflammatory effects of CatC in various disease processes that are mainly mediated by the activation of neutrophil serine proteinases. Moreover, tumor-promoting effects were ascribed to CatC. The aim of this review is to highlight current knowledge of the …

Arid1a Loss Is Associated With Increased Nrf2 Signaling In Human Head And Neck Squamous Cell Carcinomas, Vinh Nguyen, Travis P. Schrank, Michael B. Major, Bernard E. Weissman

2020-Current year OA Pubs

Prior to the next generation sequencing and characterization of the tumor genome landscape, mutations in the SWI/SNF chromatin remodeling complex and the KEAP1-NRF2 signaling pathway were underappreciated. While these two classes of mutations appeared to independently contribute to tumor development, recent reports have demonstrated a mechanistic link between these two regulatory mechanisms in specific cancer types and cell models. In this work, we expand upon these data by exploring the relationship between mutations in BAF and PBAF subunits of the SWI/SNF complex and activation of NRF2 signal transduction across many cancer types. ARID1A/B mutations were strongly associated with NRF2 transcriptional …