The International Mouse Phenotyping Consortium (IMPC): a Functional
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Genetic Heterogeneity of Usher Syndrome Type II
J7Med Genet 1996;33:753-757 753 Genetic heterogeneity of Usher syndrome type II in a Dutch population J Med Genet: first published as 10.1136/jmg.33.9.753 on 1 September 1996. Downloaded from S Pieke-Dahl, A van Aarem, A Dobin, C W R J Cremers, W J Kimberling Abstract In 1959, Hallgren' laid the foundation for the The Usher syndromes are a group ofauto- clinical definition of US in a study of 172 US somal recessive disorders characterised patients from Sweden. Hallgren' showed sig- by retinitis pigmentosa (RP) with con- nificant phenotypic heterogeneity of US by genital, stable (non-progressive) sen- describing two clinically distinct forms, Usher sorineural hearing loss. Profound deaf- syndrome type I and Usher syndrome type II. ness, RP, and no vestibular responses are Profound congenital deafness, RP, and absent features of Usher type I, whereas moder- vestibular responses was defined as Usher I, ate to severe hearing loss and RP with while those exhibiting a congenital moderate to normal vestibular function describe severe hearing loss, RP, and no associated ves- Usher type II. The gene responsible for tibular problems was defined as Usher II.2 3 most cases ofUsher II, USH2a, is on chro- Although the existence of a type of US with mosome 1q41; at least one other Usher II progressive hearing loss had been proposed,4 gene (as yet unlinked) is known to exist. there was no firm genetic evidence for a Usher III presents with a progressive separate Usher III phenotype until a group of hearing loss that can mimic the audiomet- Finnish families with a phenotype of progres- ric profile seen in Usher II. -
The USH2A C.2299Delg Mutation: Dating Its Common Origin in a Southern European Population
European Journal of Human Genetics (2010) 18, 788–793 & 2010 Macmillan Publishers Limited All rights reserved 1018-4813/10 www.nature.com/ejhg ARTICLE The USH2A c.2299delG mutation: dating its common origin in a Southern European population Elena Aller1,2, Lise Larrieu3, Teresa Jaijo1,2, David Baux3, Carmen Espino´s2, Fernando Gonza´lez-Candelas4,5,6, Carmen Na´jera7, Francesc Palau2,8, Mireille Claustres3,9,10, Anne-Franc¸oise Roux3,9 and Jose´ M Milla´n*,1,2 Usher syndrome type II is the most common form of Usher syndrome. USH2A is the main responsible gene of the three known to be disease causing. It encodes two isoforms of the protein usherin. This protein is part of an interactome that has an essential role in the development and function of inner ear hair cells and photoreceptors. The gene contains 72 exons spanning over a region of 800 kb. Although numerous mutations have been described, the c.2299delG mutation is the most prevalent in several populations. Its ancestral origin was previously suggested after the identification of a common core haplotype restricted to 250 kb in the 5¢ region that encodes the short usherin isoform. By extending the haplotype analysis over the 800 kb region of the USH2A gene with a total of 14 intragenic single nucleotide polymorphisms, we have been able to define 10 different c.2299delG haplotypes, showing high variability but preserving the previously described core haplotype. An exhaustive c.2299delG/control haplotype study suggests that the major source of variability in the USH2A gene is recombination. Furthermore, we have evidenced twice the amount of recombination hotspots located in the 500 kb region that covers the 3¢ end of the gene, explaining the higher variability observed in this region when compared with the 250 kb of the 5¢ region. -
Tumor-Associated Antigens Identified Early in Mouse Mammary Tumor Development Can Be Effective Vaccine Targets
Vaccine 37 (2019) 3552–3561 Contents lists available at ScienceDirect Vaccine journal homepage: www.elsevier.com/locate/vaccine Tumor-associated antigens identified early in mouse mammary tumor development can be effective vaccine targets ⇑ Sasha E. Stanton a, , Ekram Gad a, Lauren R. Corulli a, Hailing Lu a,1, Mary L. Disis a a Cancer Vaccine Institute, University of Washington, Seattle WA, 98109, USA article info abstract Article history: Breast cancer vaccines composed of antigens identified by serological analysis of cDNA expression Received 25 June 2018 libraries (SEREX) induce antigen specific immune responses in patients but have had disappointing clin- Received in revised form 5 April 2019 ical benefits. While many attempts to modify the adjuvants and vaccine method have been tried, one Accepted 9 May 2019 issue not addressed was whether the SEREX tumor-associated antigens identified from late stages of dis- Available online 21 May 2019 ease were ideal targets. We questioned in the transgenic TgMMTV-neu mouse model whether the antigen repertoire is distinct between early and late stage breast cancer and whether the antigens identified via Keywords: SEREX from transgenic mice with early or late stage tumors would elicit differential anti-tumor effects to Breast cancer prevention address this question. Vaccine antigens Th1 Three early stage antigens, Pdhx, Stk39, and Otud6B, were identified from a SEREX screen of mice prior DNA vaccines to development of palpable lesions. Formulated into a vaccine, each early antigen inhibited tumor growth Mouse mammary tumor models (p < 0.0001). The antigens identified from mice with late stage tumors (Swap70, Gsn, and Arhgef2) were unable to inhibit tumor growth when used as vaccines (for example Gsn p = 0.26). -
Autism Ontario Genetics Webinar EN.Pdf
Autism Ontario Genetics Webinar Thursday October 29, 2020 12:00 – 1:00 pm Panelist Stephen Scherer, PhD - Scientist Ny Hoang, MS, CGC – Genetic Counsellor Ryan Yuen, PhD - Scientist Evdokia Anagnostou, MD - Child Neurologist Autism Spectrum Disorders weak genetic factor Complex Multifactorial Condition strong genetic factor environmental factors Genetic contribution is highly variable Strong genetic Moderate genetic Weaker genetic factor factor factor Examples of genetic factors: SHANK3, NRXN1, CHD8, ARID1B, 16p13.11, 22q11 Genetic contribution is a biological difference chromosome Cell DNA sequence Protein Genetic contribution is a biological difference chromosome Cell DNA sequence genetic variant Protein not working Protein Protein not working DNA sequence genetic variant Deletions & Duplications Single Nucleotide Variations 1q21.1 deletions/ duplications CHD8, ARID1B, SCN2A, SYNGAP1, 16p13.11 deletions/ duplications SHANK3, ANK2, GRIN2B, CHD2 NRXN3, ASTN2, MBD5, PTCHD1 DNA sequence genetic variant Repeat Expansions Example: Fragile X syndrome (FMR1) CGGCGGCGGCGGCGG Normal repeat size: 5-40 CGGCGGCGGCGGCGGCGGCGGCGGCGG Syndrome repeat size: >200 DNA sequence genetic variant Repeat Expansions Fragile X syndrome (FMR1), repeat >200 • Disorders linked to well- CGG defined repeat pattern (motif) Friedreich Ataxia (FXN), repeat >100 • Only one pattern per disorder GAA • Myotonic dystrophy Type 1 (DMPK), repeat >50 Normal repeat size range CTG known Huntington’s Disease (HTT), repeat >35 CAG Spinocerebellar Ataxia Type 10 (ATXN10), repeat >800 -
ARID5B As a Critical Downstream Target of the TAL1 Complex That Activates the Oncogenic Transcriptional Program and Promotes T-Cell Leukemogenesis
Downloaded from genesdev.cshlp.org on October 10, 2021 - Published by Cold Spring Harbor Laboratory Press ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis Wei Zhong Leong,1 Shi Hao Tan,1 Phuong Cao Thi Ngoc,1 Stella Amanda,1 Alice Wei Yee Yam,1 Wei-Siang Liau,1 Zhiyuan Gong,2 Lee N. Lawton,1 Daniel G. Tenen,1,3,4 and Takaomi Sanda1,4 1Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore; 2Department of Biological Sciences, National University of Singapore, 117543 Singapore; 3Harvard Medical School, Boston, Massachusetts 02215, USA; 4Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lym- phoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich interactive domain 5B (ARID5B) as a col- laborating oncogenic factor involved in the transcriptional program in T-ALL. ARID5B expression is down-regulated at the double-negative 2–4 stages in normal thymocytes, while it is induced by the TAL1 complex in human T-ALL cells. The enhancer located 135 kb upstream of the ARID5B gene locus is activated under a superenhancer in T-ALL cells but not in normal T cells. Notably, ARID5B-bound regions are associated predominantly with active tran- scription. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression. -
Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’S Biological Network Based on Systematic Pharmacology
ORIGINAL RESEARCH published: 25 June 2021 doi: 10.3389/fphar.2021.601846 Exploring the Regulatory Mechanism of Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’s Biological Network Based on Systematic Pharmacology Kailin Yang 1†, Liuting Zeng 1†, Anqi Ge 2†, Yi Chen 1†, Shanshan Wang 1†, Xiaofei Zhu 1,3† and Jinwen Ge 1,4* Edited by: 1 Takashi Sato, Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of 2 Tokyo University of Pharmacy and Life Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China, Galactophore Department, The First 3 Sciences, Japan Hospital of Hunan University of Chinese Medicine, Changsha, China, School of Graduate, Central South University, Changsha, China, 4Shaoyang University, Shaoyang, China Reviewed by: Hui Zhao, Capital Medical University, China Background: Clinical research found that Hedysarum Multijugum Maxim.-Chuanxiong Maria Luisa Del Moral, fi University of Jaén, Spain Rhizoma Compound (HCC) has de nite curative effect on cerebral ischemic diseases, *Correspondence: such as ischemic stroke and cerebral ischemia-reperfusion injury (CIR). However, its Jinwen Ge mechanism for treating cerebral ischemia is still not fully explained. [email protected] †These authors share first authorship Methods: The traditional Chinese medicine related database were utilized to obtain the components of HCC. The Pharmmapper were used to predict HCC’s potential targets. Specialty section: The CIR genes were obtained from Genecards and OMIM and the protein-protein This article was submitted to interaction (PPI) data of HCC’s targets and IS genes were obtained from String Ethnopharmacology, a section of the journal database. -
SARS-Cov-2 Entry Protein TMPRSS2 and Its Homologue, TMPRSS4
bioRxiv preprint doi: https://doi.org/10.1101/2021.04.26.441280; this version posted April 26, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 SARS-CoV-2 Entry Protein TMPRSS2 and Its 2 Homologue, TMPRSS4 Adopts Structural Fold Similar 3 to Blood Coagulation and Complement Pathway 4 Related Proteins ∗,a ∗∗,b b 5 Vijaykumar Yogesh Muley , Amit Singh , Karl Gruber , Alfredo ∗,a 6 Varela-Echavarría a 7 Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México b 8 Institute of Molecular Biosciences, University of Graz, Graz, Austria 9 Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes TMPRSS2 receptor to enter target human cells and subsequently causes coron- avirus disease 19 (COVID-19). TMPRSS2 belongs to the type II serine proteases of subfamily TMPRSS, which is characterized by the presence of the serine- protease domain. TMPRSS4 is another TMPRSS member, which has a domain architecture similar to TMPRSS2. TMPRSS2 and TMPRSS4 have been shown to be involved in SARS-CoV-2 infection. However, their normal physiological roles have not been explored in detail. In this study, we analyzed the amino acid sequences and predicted 3D structures of TMPRSS2 and TMPRSS4 to under- stand their functional aspects at the protein domain level. Our results suggest that these proteins are likely to have common functions based on their conserved domain organization. -
De Novo POGZ Mutations in Sporadic
Matsumura et al. Journal of Molecular Psychiatry (2016) 4:1 DOI 10.1186/s40303-016-0016-x SHORT REPORT Open Access De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ Kensuke Matsumura1, Takanobu Nakazawa2*, Kazuki Nagayasu2, Nanaka Gotoda-Nishimura1, Atsushi Kasai1, Atsuko Hayata-Takano1, Norihito Shintani1, Hidenaga Yamamori3, Yuka Yasuda3, Ryota Hashimoto3,4 and Hitoshi Hashimoto1,2,4 Abstract Background: A spontaneous de novo mutation is a new mutation appeared in a child that neither the parent carries. Recent studies suggest that recurrent de novo loss-of-function mutations identified in patients with sporadic autism spectrum disorder (ASD) play a key role in the etiology of the disorder. POGZ is one of the most recurrently mutated genes in ASD patients. Our laboratory and other groups have recently found that POGZ has at least 18 independent de novo possible loss-of-function mutations. Despite the apparent importance, these mutations have never previously been assessed via functional analysis. Methods: Using wild-type, the Q1042R-mutated, and R1008X-mutated POGZ, we performed DNA-binding experiments for proteins that used the CENP-B box sequence in vitro. Data were statistically analyzed by one-way ANOVA followed by Tukey-Kramer post hoc tests. Results: This study reveals that ASD-associated de novo mutations (Q1042R and R1008X) in the POGZ disrupt its DNA-binding activity. Conclusions: Here, we report the first functional characterization of de novo POGZ mutations identified in sporadic ASD cases. These findings provide important insights into the cellular basis of ASD. Keywords: Autism spectrum disorder, Recurrent mutation, De novo mutation, POGZ, DNA-binding activity Background including CHD8, ARID1B, SYNGAP1, DYRK1A, SCN2A, The genetic etiology of autism spectrum disorder (ASD) ANK2, ADNP, DSCAM, CHD2, KDM5B, SUV420H1, remains poorly understood. -
Mutational Landscape Differences Between Young-Onset and Older-Onset Breast Cancer Patients Nicole E
Mealey et al. BMC Cancer (2020) 20:212 https://doi.org/10.1186/s12885-020-6684-z RESEARCH ARTICLE Open Access Mutational landscape differences between young-onset and older-onset breast cancer patients Nicole E. Mealey1 , Dylan E. O’Sullivan2 , Joy Pader3 , Yibing Ruan3 , Edwin Wang4 , May Lynn Quan1,5,6 and Darren R. Brenner1,3,5* Abstract Background: The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours. Methods: In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined differences with 949 older-onset tumours (> 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages “deconstructSigs” and “SomaticSignatures” to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset. Results: Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while young- onset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for young- onset tumours, and a higher proportion of these mutations were C > A mutations, but a lower proportion were C > T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database. -
Co-Occupancy by Multiple Cardiac Transcription Factors Identifies
Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart Aibin Hea,b,1, Sek Won Konga,b,c,1, Qing Maa,b, and William T. Pua,b,2 aDepartment of Cardiology and cChildren’s Hospital Informatics Program, Children’s Hospital Boston, Boston, MA 02115; and bHarvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 Edited by Eric N. Olson, University of Texas Southwestern, Dallas, TX, and approved February 23, 2011 (received for review November 12, 2010) Identification of genomic regions that control tissue-specific gene study of a handful of model genes (e.g., refs. 7–10), it has not been expression is currently problematic. ChIP and high-throughput se- evaluated using unbiased, genome-wide approaches. quencing (ChIP-seq) of enhancer-associated proteins such as p300 In this study, we used a modified ChIP-seq approach to define identifies some but not all enhancers active in a tissue. Here we genome wide the binding sites of these cardiac TFs (1). We show that co-occupancy of a chromatin region by multiple tran- provide unbiased support for collaborative TF interactions in scription factors (TFs) identifies a distinct set of enhancers. GATA- driving cardiac gene expression and use this principle to show that chromatin co-occupancy by multiple TFs identifies enhancers binding protein 4 (GATA4), NK2 transcription factor-related, lo- with cardiac activity in vivo. The majority of these multiple TF- cus 5 (NKX2-5), T-box 5 (TBX5), serum response factor (SRF), and “ binding loci (MTL) enhancers were distinct from p300-bound myocyte-enhancer factor 2A (MEF2A), here referred to as cardiac enhancers in location and functional properties. -
Supplementary Materials
Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine -
Deubiquitylases in Developmental Ubiquitin Signaling and Congenital Diseases
Cell Death & Differentiation (2021) 28:538–556 https://doi.org/10.1038/s41418-020-00697-5 REVIEW ARTICLE Deubiquitylases in developmental ubiquitin signaling and congenital diseases 1 1,2 1 Mohammed A. Basar ● David B. Beck ● Achim Werner Received: 16 October 2020 / Revised: 20 November 2020 / Accepted: 24 November 2020 / Published online: 17 December 2020 This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020 Abstract Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate’s stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have fi 1234567890();,: 1234567890();,: identi ed mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.