Medicine and Health Sciences Commons^™

Self-Hybridization In Leishmania Major, Tiago R Ferreira, Ehud Inbar, Jahangheer Shaik, Brendan M Jeffrey, Kashinath Ghosh, Deborah E. Dobson, Stephen M. Beverley, David Sacks

2020-Current year OA Pubs

Genetic exchange between different

Recurrent Switch 2 Domain Rac2 Mutations In Intravascular Large B-Cell Lymphoma, Rohan Kodgule, Jie Chen, Pooja Khonde, Joshua Robinson, Amy D'Albora, Lisa Cook, Catrina C Fronick, Robert Fulton, Sridhar Nonavinkere Srivatsan, Patrick J Cimino, Eric J Duncavage

2020-Current year OA Pubs

No abstract provided.

Stat3 Gain-Of-Function Mutations Connect Leukemia With Autoimmune Disease By Pathological Nkg2dhi Cd8+ T Cell Dysregulation And Accumulation, Etienne Masle-Farquhar, Megan A Cooper, Tiphanie P Vogel, Et Al.

2020-Current year OA Pubs

The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co-existing autoimmunity. To investigate whether these mutations are the cause or consequence of CD8

Defective Proteostasis In Induced Pluripotent Stem Cell Models Of Frontotemporal Lobar Degeneration, Sidhartha Mahali, Rita Martinez, Melvin King, Anthony Verbeck, Oscar Harari, Bruno A Benitez, Kanta Horie, Chihiro Sato, Sally Temple, Celeste M Karch

2020-Current year OA Pubs

Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the accumulation of protein, which can be toxic to cells and tissue. In a subset of frontotemporal lobar degeneration with tau pathology (FTLD-tau) cases, pathogenic mutations in the microtubule-associated protein tau (MAPT) gene are sufficient to cause tau accumulation and neurodegeneration. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. Here, we show that molecular networks associated with lysosomal biogenesis and autophagic function are disrupted in brains from FTLD-tau patients carrying a MAPT p.R406W mutation. We …

The Clinical Landscape Of Cell-Free Dna Alterations In 1671 Patients With Advanced Biliary Tract Cancer, J E Berchuck, B Tan, Et Al.

2020-Current year OA Pubs

BACKGROUND: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology.

PATIENTS AND METHODS: We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA-tumor concordance and the association of cfDNA variant …

A Sarm1-Mitochondrial Feedback Loop Drives Neuropathogenesis In A Charcot-Marie-Tooth Disease Type 2a Rat Model, Yurie Sato-Yamada, Amy Strickland, Yo Sasaki, Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt

2020-Current year OA Pubs

Charcot-Marie-Tooth disease type 2A (CMT2A) is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying the axonal pathology is unknown. Sterile α and Toll/IL-1 receptor motif-containing 1 (SARM1), the central executioner of axon degeneration, can induce neuropathy and is activated by dysfunctional mitochondria. We tested the role of SARM1 in a rat model carrying a dominant CMT2A mutation (Mfn2H361Y) that exhibits progressive dying-back axonal degeneration, neuromuscular junction (NMJ) abnormalities, muscle atrophy, and mitochondrial abnormalities - all hallmarks of the human disease. We generated Sarm1-KO (Sarm1-/-) and …

Identification Of A Novel Large Multigene Deletion And A Frameshift Indel In Pde6b As The Underlying Cause Of Early-Onset Recessive Rod-Cone Degeneration, Riccardo Sangermano, Pooja Biswas, Lori S Sullivan, Emily M Place, Shyamanga Borooah, Juerg Straubhaar, Eric A Pierce, Stephen P Daiger, Kinga M Bujakowska, Radha Ayaggari

Journal Articles

A family, with two affected identical twins with early-onset recessive inherited retinal degeneration, was analyzed to determine the underlying genetic cause of pathology. Exome sequencing revealed a rare and previously reported causative variant (c.1923_1969delinsTCTGGG; p.Asn643Glyfs*29) in the

Diptoindonesin G Is A Middle Domain Hsp90 Modulator For Cancer Treatment, Kristine Donahue, Haibo Xie, Miyang Li, Ang Gao, Min Ma, Yidan Wang, Rose Tipton, Nicole Semanik, Tina Primeau, Shunqiang Li, Lingjun Li, Weiping Tang, Wei Xu

2020-Current year OA Pubs

HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (K

Comprehensive Transcriptomic Analysis Of Vista In Acute Myeloid Leukemia: Insights Into Its Prognostic Value, Simona Pagliuca, Carmelo Gurnari, Keman Zhang, Tariq Kewan, Waled Bahaj, Minako Mori, Ishani Nautiyal, Marie Thérèse Rubio, Francesca Ferraro, Jaroslaw P Maciejewski, Li Wang, Valeria Visconte

2020-Current year OA Pubs

The V-domain Ig suppressor of T-cell activation (VISTA) has been recognized as a critical negative regulator of antitumor immune response and is gaining growing interest as a potential pharmacological target in immunotherapy. This molecule is highly expressed in hematopoietic stem cells and myeloid compartment, and it has been found upmodulated in acute myeloid leukemia (AML). However, VISTA-associated immune features are relatively unexplored in myeloid malignancies. Herein, we aimed to explore whether this immune checkpoint regulator could play a role in the generation of an immune escape environment in AML patients. We characterized VISTA mRNA expression levels in leukemia cell lines …

Molecular Subclasses Of Clear Cell Ovarian Carcinoma And Their Impact On Disease Behavior And Outcomes, Kelly L Bolton, Irenaeus C C Chan, Brian J Wiley, Et Al.

2020-Current year OA Pubs

PURPOSE: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.

EXPERIMENTAL DESIGN: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.

RESULTS: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). …

The Sod1-Mediated Als Phenotype Shows A Decoupling Between Age Of Symptom Onset And Disease Duration, Sarah Opie-Martin, Jennifer Jockel-Balsarotti, Taha Bali, Wade Self, Timothy Miller, Et Al.

2020-Current year OA Pubs

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight …

Emergence Of Compensatory Mutations Reveals The Importance Of Electrostatic Interactions Between Hiv-1 Integrase And Genomic Rna, Christian Shema Mugisha, Tung Dinh, Abhishek Kumar, Kasyap Tenneti, Jenna E Eschbach, Keanu Davis, Robert Gifford, Mamuka Kvaratskhelia, Sebla B Kutluay

2020-Current year OA Pubs

HIV-1 integrase (IN) has a noncatalytic function in virion maturation through its binding to the viral RNA genome (gRNA). Class II IN substitutions inhibit IN-gRNA binding and result in the formation of virions with aberrant morphologies marked by mislocalization of the gRNA between the capsid lattice and the lipid envelope. These viruses are noninfectious due to a block at an early reverse transcription stage in target cells. HIV-1 IN utilizes basic residues within its C-terminal domain (CTD) to bind to the gRNA; however, the molecular nature of how these residues mediate gRNA binding and whether other regions of IN are …

Pooled Image-Base Screening Of Mitochondria With Microraft Isolation Distinguishes Pathogenic Mitofusin 2 Mutations, Alex L Yenkin, John C Bramley, Colin L Kremitzki, Jason E Waligorski, Mariel J Liebeskind, Xinyuan E Xu, Vinay D Chandrasekaran, Maria A Vakaki, Graham W Bachman, Robi D Mitra, Jeffrey D Milbrandt, William J Buchser

2020-Current year OA Pubs

Most human genetic variation is classified as variants of uncertain significance. While advances in genome editing have allowed innovation in pooled screening platforms, many screens deal with relatively simple readouts (viability, fluorescence) and cannot identify the complex cellular phenotypes that underlie most human diseases. In this paper, we present a generalizable functional genomics platform that combines high-content imaging, machine learning, and microraft isolation in a method termed "Raft-Seq". We highlight the efficacy of our platform by showing its ability to distinguish pathogenic point mutations of the mitochondrial regulator Mitofusin 2, even when the cellular phenotype is subtle. We also show …

The Impact Of Tsc-1 And -2 Mutations On Response To Therapy In Malignant Pecoma: A Multicenter Retrospective Analysis, Lawrence Liu, Nikhil Grandhi, Yang Lyu, Xiao Zhang, Jingqin Luo, Mia Weiss, Brian Van Tine, Angela C Hirbe, Et Al.

2020-Current year OA Pubs

BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) are a diverse family of mesenchymal tumors with myomelanocytic differentiation that disproportionately affect women and can be associated with tuberous sclerosis (TS). Although mTOR inhibition is widely used as first-line treatment, it is unclear what genomic alterations exist in these tumors and how they influence the response to therapy.

METHODS: This was a multicenter study conducted at five sites within the US. The data were collected from 1 January 2004 to 31 January 2021. We conducted a retrospective analysis to identify PEComa patients with next-generation sequencing (NGS) data and compared outcomes based on mutations. …

Cross-Species Efficacy Of Enzyme Replacement Therapy For Cln1 Disease In Mice And Sheep, Hemanth R. Nelvagal, Sophie H. Wang, Elizabeth M. Eultgen, Keigo Takashash, Steven Q. Le, Rachel Nesbitt, Joshua T. Dearborn, Patricia I. Dickson, Mark S. Sands, Jonathan D. Cooper, Et Al.

2020-Current year OA Pubs

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient …

A Dpagt1 Missense Variant Causes Degenerative Retinopathy Without Myasthenic Syndrome In Mice, Lillian F Hyde, Yang Kong, Lihong Zhao, Sriganesh Ramachandra Rao, Jieping Wang, Lisa Stone, Andrew Njaa, Gayle B. Collin, Mark P. Krebs, Bo Chang, Steven J Fliesler, Patsy M. Nishina, Juergen K. Naggert

Faculty Research 2022

Congenital disorders of glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid-linked oligosaccharides and their transfer to proteins. CDGs usually affect multiple organ systems and vary in presentation, even within families. There is currently no cure, and treatment is aimed at ameliorating symptoms and improving quality of life. Here, we describe a chemically induced mouse mutant,

Genetic Quality: A Complex Issue For Experimental Study Reproducibility., Atsushi Yoshiki, Gregory Ballard, Ana V Perez

Faculty Research 2022

Laboratory animal research involving mice, requires consideration of many factors to be controlled. Genetic quality is one factor that is often overlooked but is essential for the generation of reproducible experimental results. Whether experimental research involves inbred mice, spontaneous mutant, or genetically modified strains, exercising genetic quality through careful breeding, good recordkeeping, and prudent quality control steps such as validation of the presence of mutations and verification of the genetic background, will help ensure that experimental results are accurate and that reference controls are representative for the particular experiment. In this review paper, we will discuss various techniques used for …

Telomere Biology Disorders: Time For Moving Towards The Clinic?, Luis F Z Batista, Inderjeet Dokal, Roy Parker

2020-Current year OA Pubs

Telomere biology disorders (TBDs) are a group of rare diseases caused by mutations that impair telomere maintenance. Mutations that cause reduced levels of TERC/hTR, the telomerase RNA component, are found in most TBD patients and include loss-of-function mutations in hTR itself, in hTR-binding proteins [NOP10, NHP2, NAF1, ZCCHC8, and dyskerin (DKC1)], and in proteins required for hTR processing (PARN). These patients show diverse clinical presentations that most commonly include bone marrow failure (BMF)/aplastic anemia (AA), pulmonary fibrosis, and liver cirrhosis. There are no curative therapies for TBD patients. An understanding of hTR biogenesis, maturation, and degradation has identified pathways and …

Functional Assessment Of Missense Variants In The Abcc6 Gene Implicated In Pseudoxanthoma Elasticum, A Heritable Ectopic Mineralization Disorder., Luke Kowal, Jianhe Huang, Hongbin Luo, Jagmohan Singh, Adam E Snook, Jouni Uitto, Qiaoli Li

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder, is caused by inactivating mutations in the ABCC6 gene. The encoded protein, ABCC6, a transmembrane transporter, has a specialized efflux function in hepatocytes by contributing to plasma levels of inorganic pyrophosphate, a potent inhibitor of mineralization in soft connective tissues. Reduced plasma inorganic pyrophosphate levels underlie the ectopic mineralization in pseudoxanthoma elasticum. In this study, we characterized the pathogenicity of three human ABCC6 missense variants using an adenovirus-mediated liver-specific ABCC6 transgene expression system in an Abcc6

Proteomic And Phosphoproteomic Landscapes Of Acute Myeloid Leukemia, Michael H Kramer, Qiang Zhang, Robert Sprung, Ryan B Day, Petra Erdmann-Gilmore, Yang Li, Ziheng Xu, Nichole M Helton, Daniel R George, Yiling Mi, Peter Westervelt, Jacqueline E Payton, Sai M Ramakrishnan, Christopher A Miller, Daniel C Link, John F Dipersio, Matthew J Walter, R Reid Townsend, Timothy J Ley

2020-Current year OA Pubs

We have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow-derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate-dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. …

Systemic Chemotherapies Retain Antitumor Activity In Desmoid Tumors Independent Of Specific Mutations In Ctnnb1 Or Apc: A Multi-Institutional Retrospective Study, Michael J Nathenson, Katharina Feister, Et Al

2020-Current year OA Pubs

PURPOSE: Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments.

EXPERIMENTAL DESIGN: We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or next-generation sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), …

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, …

Comparative Risks Of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease, Ellen S. Regalado, Alan C. Braverman, Et Al.

2020-Current year OA Pubs

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, …

Making The Rounds: Exploring The Role Of Circulating Tumor Dna (Ctdna) In Non-Small Cell Lung Cancer, Misty Dawn Shields, Kevin Chen, Giselle Dutcher, Ishika Patel, Bruna Pellini

2020-Current year OA Pubs

Advancements in the clinical practice of non-small cell lung cancer (NSCLC) are shifting treatment paradigms towards increasingly personalized approaches. Liquid biopsies using various circulating analytes provide minimally invasive methods of sampling the molecular content within tumor cells. Plasma-derived circulating tumor DNA (ctDNA), the tumor-derived component of cell-free DNA (cfDNA), is the most extensively studied analyte and has a growing list of applications in the clinical management of NSCLC. As an alternative to tumor genotyping, the assessment of oncogenic driver alterations by ctDNA has become an accepted companion diagnostic via both single-gene polymerase chain reactions (PCR) and next-generation sequencing (NGS) for …

Disease-Associated Mutations Within The Yeast Dnajb6 Homolog Sis1 Slow Conformer-Specific Substrate Processing And Can Be Corrected By The Modulation Of Nucleotide Exchange Factors, Ankan K Bhadra, Michael J Rau, Jil A Daw, James A J Fitzpatrick, Conrad C Weihl, Heather L True

2020-Current year OA Pubs

Molecular chaperones, or heat shock proteins (HSPs), protect against the toxic misfolding and aggregation of proteins. As such, mutations or deficiencies within the chaperone network can lead to disease. Dominant mutations within DNAJB6 (Hsp40)-an Hsp70 co-chaperone-lead to a protein aggregation-linked myopathy termed Limb-Girdle Muscular Dystrophy Type D1 (LGMDD1). Here, we used the yeast prion model client in conjunction with in vitro chaperone activity assays to gain mechanistic insights into the molecular basis of LGMDD1. Here, we show how mutations analogous to those found in LGMDD1 affect Sis1 (a functional homolog of human DNAJB6) function by altering the structure of client …

Discovery And Validation Of Dominantly Inherited Alzheimer's Disease Mutations In Populations From Latin America, Leonel Tadao Takada, Bhagyashri D Burgute, Ellen Ziegemeier, Jennifer Petranek, Carlos Cruchaga, Maria Victoria Fernández, Eric Mcdade, Randall J Bateman, Celeste M Karch, Jorge J Llibre-Guerra, Et Al.

2020-Current year OA Pubs

BACKGROUND: In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations.

METHODS: Clinical data was collected from LatAm families at risk …

Patient With Multiple Genetically Distinct Thyroid Nodules Including Papillary Thyroid Carcinoma Harboring Novel Ywhag-Braf Fusion, Ruihe Lin, Zi-Xuan Wang, Elizabeth Cottrill, Nitika Badjatia, Stacey Gargano

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Next-generation sequencing (NGS) analysis of thyroid samples aids in risk stratification of cytologically indeterminate nodules and contributes to our understanding of molecular mechanisms in thyroid neoplasia. Several genes, including BRAF, RAS, and EIF1AX, are known to play a role in thyroid tumorigenesis. Here we report a case of papillary thyroid carcinoma (PTC) in which a single lesion harbored a novel YWHAG-BRAF fusion and EIF1AX mutation and displayed mixed morphological findings. The patient is a 74-year-old female with multiple incidentally discovered thyroid nodules, two of which were sampled by ultrasound-guided fine needle aspiration (FNA). Cytologic diagnosis for both nodules was suspicious …

Design Of A Randomized, Placebo-Controlled, Phase 3 Trial Of Tofersen Initiated In Clinically Presymptomatic Sod1 Variant Carriers: The Atlas Study, Michael Benatar, Robert C Bucelli, Et Al.

2020-Current year OA Pubs

Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of …

Mechanism Of Voltage Sensing In Ca2+- And Voltage-Activated K + (Bk) Channels, Willy Carrasquel-Ursulaez, Ignacio Segura, Ignacio Díaz-Franulic, Felipe Echeverría, Yenisleidy Lorenzo-Ceballos, Nicolás Espinoza, Maximiliano Rojas, Jose Antonio Garate, Eduardo Perozo, Osvaldo Alvarez, Fernando D Gonzalez-Nilo, Ramón Latorre, Valeria Marquez-Miranda

2020-Current year OA Pubs

In neurosecretion, allosteric communication between voltage sensors and Ca

Identification Of Arhgef12 And Prkci As Genetic Modifiers Of Retinal Dysplasia In The Crb1rd8 Mouse Model., Sonia M Weatherly, Gayle B. Collin, Jeremy R. Charette, Lisa Stone, Nattaya Damkham, Lillian F Hyde, James G Peterson, Wanda L. Hicks, Gregory W. Carter, Juergen K. Naggert, Mark P. Krebs, Patsy M. Nishina

Faculty Research 2022

Mutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, …