Genetic Phenomena Commons^™

Chemotherapy Coupled To Macrophage Inhibition Induces T-Cell And B-Cell Infiltration And Durable Regression In Triple-Negative Breast Cancer, Swarnima Singh, Nigel Lee, Diego A Pedroza, Igor L Bado, Clark Hamor, Licheng Zhang, Sergio Aguirre, Jingyuan Hu, Yichao Shen, Yitian Xu, Yang Gao, Na Zhao, Shu-Hsia Chen, Ying-Wooi Wan, Zhandong Liu, Jeffrey T Chang, Daniel Hollern, Charles M Perou, Xiang H F Zhang, Jeffrey M Rosen

Duncan NRI Faculty and Staff Publications

Immunosuppressive elements within the tumor microenvironment, such as tumor-associated macrophages (TAM), can present a barrier to successful anti-tumor responses by cytolytic T cells. Here we employed preclinical syngeneic p53 null mouse models of triple-negative breast cancer (TNBC) to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose cyclophosphamide coupled with the pharmacologic inhibition of TAMs using either a small molecule CSF1R inhibitor or an anti-CSF1R antibody. This therapeutic combination was effective in treating several highly aggressive TNBC murine mammary tumor and lung metastasis models. Single cell RNA sequencing characterized tumor-infiltrating lymphocytes (TIL) including helper T cells and antigen-presenting …

De Novo Fzr1 Loss-Of-Function Variants Cause Developmental And Epileptic Encephalopathies, Sathiya N Manivannan, Jolien Roovers, Noor Smal, Candace T Myers, Dilsad Turkdogan, Filip Roelens, Oguz Kanca, Hyung-Lok Chung, Tasja Scholz, Katharina Hermann, Tatjana Bierhals, Hande S Caglayan, Hannah Stamberger, Mae Working Group Of Euroepinomics Res Consortium, Heather Mefford, Peter De Jonghe, Shinya Yamamoto, Sarah Weckhuysen, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of …

Parental Mosaicism For Apparent De Novo Genetic Variants: Scope, Detection, And Counseling Challenges, Roni Zemet, Ignatia B Van Den Veyver, Paweł Stankiewicz

Duncan NRI Faculty and Staff Publications

The disease burden of de novo mutations (DNMs) has been evidenced only recently when the common application of next-generation sequencing technologies enabled their reliable and affordable detection through family-based clinical exome or genome sequencing. Implementation of exome sequencing into prenatal diagnostics revealed that up to 63% of pathogenic or likely pathogenic variants associated with fetal structural anomalies are apparently de novo, primarily for autosomal dominant disorders. Apparent DNMs have been considered to primarily occur as germline or zygotic events, with consequently negligible recurrence risks. However, there is now evidence that a considerable proportion of them are in fact inherited from …

Modelmatcher: A Scientist-Centric Online Platform To Facilitate Collaborations Between Stakeholders Of Rare And Undiagnosed Disease Research, J Michael Harnish, Lucian Li, Sanja Rogic, Guillaume Poirier-Morency, Seon-Young Kim, Kym M Boycott, Michael F Wangler, Hugo J Bellen, Philip Hieter, Paul Pavlidis, Zhandong Liu, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Next-generation sequencing is a prevalent diagnostic tool for undiagnosed diseases and has played a significant role in rare disease gene discovery. While this technology resolves some cases, others are given a list of possibly damaging genetic variants necessitating functional studies. Productive collaborations between scientists, clinicians, and patients (affected individuals) can help resolve such medical mysteries, and provide insights into in vivo function of human genes. Furthermore, facilitating interactions between scientists and research funders, including non-profit organizations or commercial entities, can dramatically reduce the time to translate discoveries from bench to bedside. Several systems designed to connect clinicians and researchers with …

Discovery Of Potent Bet Bromodomain 1 Stereoselective Inhibitors Using Dna-Encoded Chemical Library Selections, Ram K Modukuri, Zhifeng Yu, Zhi Tan, Hai Minh Ta, Melek Nihan Ucisik, Zhuang Jin, Justin L Anglin, Kiran L Sharma, Pranavanand Nyshadham, Feng Li, Kevin Riehle, John C Faver, Kevin Duong, Sureshbabu Nagarajan, Nicholas Simmons, Stephen S Palmer, Mingxing Teng, Damian W Young, Joanna S Yi, Choel Kim, Martin M Matzuk

Duncan NRI Faculty and Staff Publications

BRDT, BRD2, BRD3, and BRD4 comprise the bromodomain and extraterminal (BET) subfamily which contain two similar tandem bromodomains (BD1 and BD2). Selective BD1 inhibition phenocopies effects of tandem BET BD inhibition both in cancer models and, as we and others have reported of BRDT, in the testes. To find novel BET BD1 binders, we screened >4.5 billion molecules from our DNA-encoded chemical libraries with BRDT-BD1 or BRDT-BD2 proteins in parallel. A compound series enriched only by BRDT-BD1 was resynthesized off-DNA, uncovering a potent chiral compound, CDD-724, with >2,000-fold selectivity for inhibiting BRDT-BD1 over BRDT-BD2. CDD-724 stereoisomers exhibited remarkable differences in …

Biliverdin Reductase Bridges Focal Adhesion Kinase To Src To Modulate Synaptic Signaling, Chirag Vasavda, Evan R Semenza, Jason Liew, Ruchita Kothari, Ryan S Dhindsa, Shruthi Shanmukha, Anthony Lin, Robert Tokhunts, Cristina Ricco, Adele M Snowman, Lauren Albacarys, Francesco Pastore, Cristian Ripoli, Claudio Grassi, Eugenio Barone, Michael D Kornberg, Xinzhong Dong, Bindu D Paul, Solomon H Snyder

Duncan NRI Faculty and Staff Publications

Synapses connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. Synaptic function and plasticity—the neuronal process of adapting to diverse and variable inputs—depend on the dynamic nature of synaptic molecular components, which is mediated in part by cell adhesion signaling pathways. Here, we found that the enzyme biliverdin reductase (BVR) physically links together key focal adhesion signaling molecules at the synapse. BVR-null (BVR−/−) mice exhibited substantial deficits in learning and memory on neurocognitive tests, and hippocampal slices in which BVR was postsynaptically depleted showed deficits in electrophysiological responses to stimuli. …

Cross-Species Genetic Screens Identify Transglutaminase 5 As A Regulator Of Polyglutamine-Expanded Ataxin-1, Won-Seok Lee, Ismael Al-Ramahi, Hyun-Hwan Jeong, Youjin Jang, Tao Lin, Carolyn J Adamski, Laura A Lavery, Smruti Rath, Ronald Richman, Vitaliy V Bondar, Elizabeth Alcala, Jean-Pierre Revelli, Harry T Orr, Zhandong Liu, Juan Botas, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length–dependent manner, …

Reduction Of Mutant Atxn1 Rescues Premature Death In A Conditional Sca1 Mouse Model, James P Orengo, Larissa Nitschke, Meike E Van Der Heijden, Nicholas A Ciaburri, Harry T Orr, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder. As disease progresses, motor neurons are affected, and their dysfunction contributes toward the inability to maintain proper respiratory function, a major driving force for premature death in SCA1. To investigate the isolated role of motor neurons in SCA1, we created a conditional SCA1 (cSCA1) mouse model. This model suppresses expression of the pathogenic SCA1 allele with a floxed stop cassette. cSCA1 mice crossed to a ubiquitous Cre line recapitulate all the major features of the original SCA1 mouse model; however, they took twice as long to develop. We found that …

Clinical Diagnosis Of Metabolic Disorders Using Untargeted Metabolomic Profiling And Disease-Specific Networks Learned From Profiling Data, Lillian R Thistlethwaite, Xiqi Li, Lindsay C Burrage, Kevin Riehle, Joseph G Hacia, Nancy Braverman, Michael F Wangler, Marcus J Miller, Sarah H Elsea, Aleksandar Milosavljevic

Duncan NRI Faculty and Staff Publications

Untargeted metabolomics is a global molecular profiling technology that can be used to screen for inborn errors of metabolism (IEMs). Metabolite perturbations are evaluated based on current knowledge of specific metabolic pathway deficiencies, a manual diagnostic process that is qualitative, has limited scalability, and is not equipped to learn from accumulating clinical data. Our purpose was to improve upon manual diagnosis of IEMs in the clinic by developing novel computational methods for analyzing untargeted metabolomics data. We employed CTD, an automated computational diagnostic method that "connects the dots" between metabolite perturbations observed in individual metabolomics profiling data and modules identified …

A Combined Conduit-Bioactive Hydrogel Approach For Regeneration Of Transected Sciatic Nerves, Cheuk Sun Edwin Lai, Viridiana Leyva-Aranda, Victoria H Kong, Tania L Lopez-Silva, Adam C Farsheed, Carlo D Cristobal, Joseph W R Swain, Hyun Kyoung Lee, Jeffrey D Hartgerink

Duncan NRI Faculty and Staff Publications

Transected peripheral nerve injury (PNI) affects the quality of life of patients, which leads to socioeconomic burden. Despite the existence of autografts and commercially available nerve guidance conduits (NGCs), the complexity of peripheral nerve regeneration requires further research in bioengineered NGCs to improve surgical outcomes. In this work, we introduce multidomain peptide (MDP) hydrogels, as intraluminal fillers, into electrospun poly(ε-caprolactone) (PCL) conduits to bridge 10 mm rat sciatic nerve defects. The efficacy of treatment groups was evaluated by electromyography and gait analysis to determine their electrical and motor recovery. We then studied the samples' histomorphometry with immunofluorescence staining and automatic …

Dynamics Of Huntingtin Protein Interactions In The Striatum Identifies Candidate Modifiers Of Huntington Disease, Todd M Greco, Christopher Secker, Eduardo Silva Ramos, Joel D Federspiel, Jeh-Ping Liu, Alma M Perez, Ismael Al-Ramahi, Jeffrey P Cantle, Jeffrey B Carroll, Juan Botas, Scott O Zeitlin, Erich E Wanker, Ileana M Cristea

Duncan NRI Faculty and Staff Publications

Huntington’s disease (HD) is a monogenic neurodegenerative disorder with one causative gene, huntingtin (HTT). Yet, HD pathobiology is multifactorial, suggesting that cellular factors influence disease progression. Here, we define HTT protein-protein interactions (PPIs) perturbed by the mutant protein with expanded polyglutamine in the mouse striatum, a brain region with selective HD vulnerability. Using metabolically labeled tissues and immunoaffinity purification-mass spectrometry, we establish that polyglutamine-dependent modulation of HTT PPI abundances and relative stability starts at an early stage of pathogenesis in a Q140 HD mouse model. We identify direct and indirect PPIs that are also genetic disease modifiers using in-cell two-hybrid …

Loss-Of-Function Variants In Tiam1 Are Associated With Developmental Delay, Intellectual Disability, And Seizures, Shenzhao Lu, Rebecca Hernan, Paul C Marcogliese, Yan Huang, Tracy S Gertler, Meltem Akcaboy, Shiyong Liu, Hyung-Lok Chung, Xueyang Pan, Xiaoqin Sun, Melahat Melek Oguz, Ulkühan Oztoprak, Jeroen H F De Baaij, Jelena Ivanisevic, Erin Mcginnis, Maria J Guillen Sacoto, Wendy K Chung, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in …

Disrupting The Myc-Tfeb Circuit Impairs Amino Acid Homeostasis And Provokes Metabolic Anergy, Mario R Fernandez, Franz X Schaub, Chunying Yang, Weimin Li, Seongseok Yun, Stephanie K Schaub, Frank C Dorsey, Min Liu, Meredith A Steeves, Andrea Ballabio, Alexandar Tzankov, Zhihua Chen, John M Koomen, Anders E Berglund, John L Cleveland

Duncan NRI Faculty and Staff Publications

MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA …

Drosophila Functional Screening Of De Novo Variants In Autism Uncovers Damaging Variants And Facilitates Discovery Of Rare Neurodevelopmental Diseases, Paul C Marcogliese, Samantha L Deal, Jonathan Andrews, J Michael Harnish, V Hemanjani Bhavana, Hillary K Graves, Sharayu Jangam, Xi Luo, Ning Liu, Danqing Bei, Yu-Hsin Chao, Brooke Hull, Pei-Tseng Lee, Hongling Pan, Pradnya Bhadane, Mei-Chu Huang, Colleen M Longley, Hsiao-Tuan Chao, Hyung-Lok Chung, Nele A Haelterman, Oguz Kanca, Sathiya N Manivannan, Linda Z Rossetti, Ryan J German, Amanda Gerard, Eva Maria Christina Schwaibold, Sarah Fehr, Renzo Guerrini, Annalisa Vetro, Eleina England, Chaya N Murali, Tahsin Stefan Barakat, Marieke F Van Dooren, Martina Wilke, Marjon Van Slegtenhorst, Gaetan Lesca, Isabelle Sabatier, Nicolas Chatron, Catherine A Brownstein, Jill A Madden, Pankaj B Agrawal, Boris Keren, Thomas Courtin, Laurence Perrin, Melanie Brugger, Timo Roser, Steffen Leiz, Frederic Tran Mau-Them, Julian Delanne, Elena Sukarova-Angelovska, Slavica Trajkova, Erik Rosenhahn, Vincent Strehlow, Konrad Platzer, Roberto Keller, Lisa Pavinato, Alfredo Brusco, Jill A Rosenfeld, Ronit Marom, Michael F Wangler, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through "humanization" rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed …

Cleavage Stimulating Factor 64 Depletion Mitigates Cardiac Fibrosis Through Alternative Polyadenylation, Rahul Neupane, Keith Youker, Hari Krishna Yalamanchili, Katarzyna A Cieslik, Harry Karmouty-Quintana, Ashrith Guha, Rajarajan A Thandavarayan

Duncan NRI Faculty and Staff Publications

Alternative polyadenylation (APA) regulates gene expression by cleavage and addition of poly(A) sequence at different polyadenylation sites (PAS) in 3'UTR, thus, generating transcript isoforms with different lengths. Cleavage stimulating factor 64 (CstF64) is an APA regulator which plays a role in PAS selection and determines the length of 3'UTR. CstF64 favors the use of proximal PAS, resulting in 3'UTR shortening, which enhances the protein expression by increasing the stability of the target genes. The aim of this study is to investigate the role of CstF64 in cardiac fibrosis, a key event leading to heart failure (HF). We determined the expression …

Fly Cell Atlas: A Single-Nucleus Transcriptomic Atlas Of The Adult Fruit Fly, Hongjie Li, Jasper Janssens, Maxime De Waegeneer, Sai Saroja Kolluru, Kristofer Davie, Vincent Gardeux, Wouter Saelens, Fabrice P A David, Maria Brbić, Katina Spanier, Jure Leskovec, Colleen N Mclaughlin, Qijing Xie, Robert C Jones, Katja Brueckner, Jiwon Shim, Sudhir Gopal Tattikota, Frank Schnorrer, Katja Rust, Todd G Nystul, Zita Carvalho-Santos, Carlos Ribeiro, Soumitra Pal, Sharvani Mahadevaraju, Teresa M Przytycka, Aaron M Allen, Stephen F Goodwin, Cameron W Berry, Margaret T Fuller, Helen White-Cooper, Erika L Matunis, Stephen Dinardo, Anthony Galenza, Lucy Erin O'Brien, Julian A T Dow, Fca Consortium, Heinrich Jasper, Brian Oliver, Norbert Perrimon, Bart Deplancke, Stephen R Quake, Liqun Luo, Stein Aerts, Devika Agarwal, Yasir Ahmed-Braimah, Michelle Arbeitman, Majd M Ariss, Jordan Augsburger, Kumar Ayush, Catherine C Baker, Torsten Banisch, Katja Birker, Rolf Bodmer, Benjamin Bolival, Susanna E Brantley, Julie A Brill, Nora C Brown, Norene A Buehner, Xiaoyu Tracy Cai, Rita Cardoso-Figueiredo, Fernando Casares, Amy Chang, Thomas R Clandinin, Sheela Crasta, Claude Desplan, Angela M Detweiler, Darshan B Dhakan, Erika Donà, Stefanie Engert, Swann Floc'hlay, Nancy George, Amanda J González-Segarra, Andrew K Groves, Samantha Gumbin, Yanmeng Guo, Devon E Harris, Yael Heifetz, Stephen L Holtz, Felix Horns, Bruno Hudry, Ruei-Jiun Hung, Yuh Nung Jan, Jacob S Jaszczak, Gregory S X E Jefferis, Jim Karkanias, Timothy L Karr, Nadja Sandra Katheder, James Kezos, Anna A Kim, Seung K Kim, Lutz Kockel, Nikolaos Konstantinides, Thomas B Kornberg, Henry M Krause, Andrew Thomas Labott, Meghan Laturney, Ruth Lehmann, Sarah Leinwand, Jiefu Li, Joshua Shing Shun Li, Kai Li, Ke Li, Liying Li, Tun Li, Maria Litovchenko, Han-Hsuan Liu, Yifang Liu, Tzu-Chiao Lu, Jonathan Manning, Anjeli Mase, Mikaela Matera-Vatnick, Neuza Reis Matias, Caitlin E Mcdonough-Goldstein, Aaron Mcgeever, Alex D Mclachlan, Paola Moreno-Roman, Norma Neff, Megan Neville, Sang Ngo, Tanja Nielsen, Caitlin E O'Brien, David Osumi-Sutherland, Mehmet Neset Özel, Irene Papatheodorou, Maja Petkovic, Clare Pilgrim, Angela Oliveira Pisco, Carolina Reisenman, Erin Nicole Sanders, Gilberto Dos Santos, Kristin Scott, Aparna Sherlekar, Philip Shiu, David Sims, Rene V Sit, Maija Slaidina, Harold E Smith, Gabriella Sterne, Yu-Han Su, Daniel Sutton, Marco Tamayo, Michelle Tan, Ibrahim Tastekin, Christoph Treiber, David Vacek, Georg Vogler, Scott Waddell, Wanpeng Wang, Rachel I Wilson, Mariana F Wolfner, Yiu-Cheung E Wong, Anthony Xie, Jun Xu, Shinya Yamamoto, Jia Yan, Zepeng Yao, Kazuki Yoda, Ruijun Zhu, Robert P Zinzen

Duncan NRI Faculty and Staff Publications

For more than 100 years, the fruit fly Drosophila melanogaster has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula Drosophilae, that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types between tissues, such as blood and muscle cells, reveals rare cell types and tissue-specific subtypes. This …

Daam2 Regulates Myelin Structure And The Oligodendrocyte Actin Cytoskeleton Through Rac1 And Gelsolin, Carlo D Cristobal, Chih-Yen Wang, Zhongyuan Zuo, Joshua A Smith, Aaron Lindeke-Myers, Hugo J Bellen, Hyun Kyoung Lee

Duncan NRI Faculty and Staff Publications

Myelin is essential to neuronal health and CNS function, and oligodendrocytes (OLs) undergo a complex process of cytoskeletal remodeling to form compact myelin sheaths. We previously discovered that a formin protein, Dishevelled associated activator of morphogenesis 2 (Daam2), suppresses OL differentiation through Wnt signaling; however, its role in cytoskeletal control remains unknown. To investigate this, we used OL-specific Daam2 conditional knockout (Daam2 cKO) mice of either sex and found myelin decompaction during an active period of myelination in postnatal development and motor coordination deficits in adulthood. Using primary OL cultures, we found Daam2-depleted OLs showed morphologic dysregulation during differentiation, suggesting …

A Multidisciplinary Approach And Consensus Statement To Establish Standards Of Care For Angelman Syndrome, Jessica Duis, Mark Nespeca, Jane Summers, Lynne Bird, Karen G C B Bindels-De Heus, M J Valstar, Marie-Claire Y De Wit, C Navis, Maartje Ten Hooven-Radstaake, Bianca M Van Iperen-Kolk, Susan Ernst, Melina Dendrinos, Terry Katz, Gloria Diaz-Medina, Akshat Katyayan, Srishti Nangia, Ronald Thibert, Daniel Glaze, Christopher Keary, Karine Pelc, Nicole Simon, Anjali Sadhwani, Helen Heussler, Anne Wheeler, Caroline Woeber, Margaret Deramus, Amy Thomas, Emily Kertcher, Lauren Devalk, Kristen Kalemeris, Kara Arps, Carol Baym, Nicole Harris, John P Gorham, Brenda L Bohnsack, Reid C Chambers, Sarah Harris, Henry G Chambers, Katherine Okoniewski, Elizabeth R Jalazo, Allyson Berent, Carlos A Bacino, Charles Williams, Anne Anderson

Duncan NRI Faculty and Staff Publications

Background: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a …

Clinical Exome Sequencing Data Reveal High Diagnostic Yields For Congenital Diaphragmatic Hernia Plus (Cdh+) And New Phenotypic Expansions Involving Cdh, Tiana M Scott, Ian M Campbell, Andres Hernandez-Garcia, Seema R Lalani, Pengfei Liu, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Duncan NRI Faculty and Staff Publications

Background: Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.

Methods: We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.

Results: Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other …

Recent Insights Into The Role Of Glia And Oxidative Stress In Alzheimer’S Disease Gained From Drosophila, Lindsey D Goodman, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Here, we discuss findings made using Drosophila on Alzheimer's disease (AD) risk and progression. Recent studies have investigated the mechanisms underlying glia-mediated neuroprotection in AD. First, we discuss a novel mechanism of glial lipid droplet formation that occurs in response to elevated reactive oxygen species in neurons. The data suggest that disruptions to this process contribute to AD risk. We further discuss novel mechanistic insights into glia-mediated Aβ42-clearance made using the fly. Finally, we highlight work that provides evidence that the aberrant accumulation of reactive oxygen species in AD may not just be a consequence of disease but contribute to …

Loss Of Irf2bpl Impairs Neuronal Maintenance Through Excess Wnt Signaling, Paul C Marcogliese, Debdeep Dutta, Shrestha Sinha Ray, Nghi D P Dang, Zhongyuan Zuo, Yuchun Wang, Di Lu, Fatima Fazal, Thomas A Ravenscroft, Hyunglok Chung, Oguz Kanca, Jijun Wan, Emilie D Douine, Undiagnosed Diseases Network, Loren D M Pena, Shinya Yamamoto, Stanley F Nelson, Matthew Might, Kathrin C Meyer, Nan Cher Yeo, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits, the Drosophila ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased wingless (wg) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction …

Sensory Processing Phenotypes In Phelan-Mcdermid Syndrome And Syngap1-Related Intellectual Disability, Ariel M Lyons-Warren, Maria C Mccormack, Jimmy L Holder

Duncan NRI Faculty and Staff Publications

Sensory processing differences are an established feature of both syndromic and non-syndromic Autism Spectrum Disorders (ASDs). Significant work has been carried out to characterize and classify specific sensory profiles in non-syndromic autism. However, it is not known if syndromic autism disorders, such as Phelan-McDermid Syndrome (PMD) or SYNGAP1-related Intellectual Disability (SYNGAP1-ID), have unique sensory phenotypes. Understanding the sensory features of these disorders is important for providing appropriate care and for understanding their underlying mechanisms. Our objective in this work was to determine the sensory processing abnormalities present in two syndromic ASDs: Phelan-McDermid Syndrome and SYNGAP1-related Intellectual …

Functional Studies Of Genetic Variants Associated With Human Diseases In Notch Signaling-Related Genes Using Drosophila, Sheng-An Yang, Jose L Salazar, David Li-Kroeger, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Rare variants in the many genes related to Notch signaling cause diverse Mendelian diseases that affect myriad organ systems. In addition, genome- and exome-wide association studies have linked common and rare variants in Notch-related genes to common diseases and phenotypic traits. Moreover, somatic mutations in these genes have been observed in many types of cancer, some of which are classified as oncogenic and others as tumor suppressive. While functional characterization of some of these variants has been performed through experimental studies, the number of ‘variants of unknown significance’ identified in patients with diverse conditions keeps increasing as high-throughput sequencing technologies …

Emerging Roles Of Alternative Cleavage And Polyadenylation (Apa) In Human Disease, Prakash Dharmalingam, Rajasekaran Mahalingam, Hari Krishna Yalamanchili, Tingting Weng, Harry Karmouty-Quintana, Ashrith Guha, Rajarajan A Thandavarayan

Duncan NRI Faculty and Staff Publications

In the messenger RNA (mRNA) maturation process, the 3'-end of pre-mRNA is cleaved and a poly(A) sequence is added, this is an important determinant of mRNA stability and its cellular functions. More than 60%-70% of human genes have three or more polyadenylation (APA) sites and can be cleaved at different sites, generating mRNA transcripts of varying lengths. This phenomenon is termed as alternative cleavage and polyadenylation (APA) and it plays role in key biological processes like gene regulation, cell proliferation, senescence, and also in various human diseases. Loss of regulatory microRNA binding sites and interactions with RNA-binding proteins leading to …

Comparison Of Treadmill Gait Between A Pediatric-Aged Individual With Syngap1-Related Intellectual Disability And A Fraternal Twin, Charles S Layne, Christopher A Malaya, David R Young, Berhard Suter, Jimmy L Holder

Duncan NRI Faculty and Staff Publications

SYNGAP1-related Intellectual Disability (SYNGAP1-ID) is a rare neurodevelopmental condition characterized by profound intellectual disability, gross motor delays, and behavioral issues. Ataxia and gait difficulties are often observed but have not yet been characterized by laboratory-based kinematic analyses. This investigation identified gait characteristics of an individual with SYNGAP1-ID and compared these with a neurotypical fraternal twin. Lower limb kinematics were collected with a 12-camera motion capture system while both participants walked on a motorized treadmill. Kinematic data were separated into strides, and stride times calculated. Sagittal plane hip, knee, and ankle joints were filtered and temporally normalized …

Quantification Of Behavioral Deficits In Developing Mice With Dystonic Behaviors., Meike E Van Der Heijden, Jason S Gill, Alejandro G Rey Hipolito, Luis E Salazar Leon, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Converging evidence from structural imaging studies in patients, the function of dystonia-causing genes, and the comorbidity of neuronal and behavioral defects all suggest that pediatric-onset dystonia is a neurodevelopmental disorder. However, to fully appreciate the contribution of altered development to dystonia, a mechanistic understanding of how networks become dysfunctional is required for early-onset dystonia. One current hurdle is that many dystonia animal models are ideally suited for studying adult phenotypes, as the neurodevelopmental features can be subtle or are complicated by broad developmental deficits. Furthermore, most assays that are used to measure dystonia are not suited for developing postnatal mice. …

Advancements In The Quest To Map, Monitor, And Manipulate Neural Circuitry, Jessica L Swanson, Pey-Shyuan Chin, Juan M Romero, Snigdha Srivastava, Joshua Ortiz-Guzman, Patrick J Hunt, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

Neural circuits and the cells that comprise them represent the functional units of the brain. Circuits relay and process sensory information, maintain homeostasis, drive behaviors, and facilitate cognitive functions such as learning and memory. Creating a functionally-precise map of the mammalian brain requires anatomically tracing neural circuits, monitoring their activity patterns, and manipulating their activity to infer function. Advancements in cell-type-specific genetic tools allow interrogation of neural circuits with increased precision. This review provides a broad overview of recombination-based and activity-driven genetic targeting approaches, contemporary viral tracing strategies, electrophysiological recording methods, newly developed calcium, and voltage indicators, and neurotransmitter/neuropeptide biosensors …

In Alzheimer-Prone Brain Regions, Metabolism And Risk-Gene Expression Are Strongly Correlated, Fengdan Ye, Quentin Funk, Elijah Rockers, Joshua M Shulman, Joseph C Masdeu, Belen Pascual

Duncan NRI Faculty and Staff Publications

Neuroimaging in the preclinical phase of Alzheimer’s disease provides information crucial to early intervention, particularly in people with a high genetic risk. Metabolic network modularity, recently applied to the study of dementia, is increased in Alzheimer’s disease patients compared with controls, but network modularity in cognitively unimpaired elderly with various risks of developing Alzheimer’s disease needs to be determined. Based on their 5-year cognitive progression, we stratified 117 cognitively normal participants (78.3 ± 4.0 years of age, 52 women) into three age-matched groups, each with a different level of risk for Alzheimer’s disease. From their fluorodeoxyglucose PET we constructed metabolic …

Recurrent Liponeurocytoma: A Case Report And Systematic Review Of The Literature, Darsh S Shah, Himanshu Sharma, Prem Patel, Arya Shetty, Collin William English, J Clay Goodman, Ashwin Viswanathan, Akash J Patel

Duncan NRI Faculty and Staff Publications

Background: Liponeurocytomas are rare neurocytic neoplasms that most often arise in the posterior fossa and affect individuals in the third and fifth decades of life. Most reported cases of this unique tumor in the literature have described a favorable clinical prognosis without recurrence. However, increasing reports of recurrent cases prompted the World Health Organization, in 2016, to recategorize the tumor from Grade I to the less favorable Grade II classification. We conducted a systematic review to identify recurrent cases of this unique tumor and to summarize differences between the primary and recurrent cases of liponeurocytoma.

Methods: A systematic review exploring …

Epithelial Morphogenesis In The Drosophila Egg Chamber Requires Parvin And Ilk, Athina Keramidioti, Evgenia Golegou, Eleni Psarra, Nikolaos Paschalidis, Konstantina Kalodimou, Shinya Yamamoto, Christos Delidakis, Katerina M Vakaloglou, Christos G Zervas

Duncan NRI Faculty and Staff Publications

Integrins are the major family of transmembrane proteins that mediate cell-matrix adhesion and have a critical role in epithelial morphogenesis. Integrin function largely depends on the indirect connection of the integrin cytoplasmic tail to the actin cytoskeleton through an intracellular protein network, the integrin adhesome. What is currently unknown is the role of individual integrin adhesome components in epithelia dynamic reorganization. Drosophila egg chamber consists of the oocyte encircled by a monolayer of somatic follicle epithelial cells that undergo specific cell shape changes. Egg chamber morphogenesis depends on a developmental array of cell-cell and cell-matrix signalling events. Recent elegant work …