DOCSLIB.ORG

Copy Number Variants at Williams–Beuren Syndrome 7Q11.23 Region

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Copy Number Variants at Williams–Beuren Syndrome 7Q11.23 Region Hum Genet (2010) 128:3–26 DOI 10.1007/s00439-010-0827-2 REVIEW ARTICLE Copy number variants at Williams–Beuren syndrome 7q11.23 region Giuseppe Merla · Nicola Brunetti-Pierri · Lucia Micale · Carmela Fusco Received: 23 February 2010 / Accepted: 13 April 2010 / Published online: 1 May 2010 © Springer-Verlag 2010 Abstract Copy number variants (CNVs) of the Williams– CNVs, including the neurocognitive phenotypes, are still Beuren syndrome (WBS) 7q11.23 region are responsible debated. Recent studies suggest that besides the role of the for neurodevelopmental disorders with multi-system genes in the deleted/duplicated interval, multiple factors involvement and variable expressivity. Typical features of such as regulatory sequences, epigenetic mechanisms, WBS microdeletion comprise a recognizable pattern of parental origin of the CNV, and nucleotide variations in the facial dysmorphisms, supravalvular aortic stenosis, connec- non-deleted/duplicated allele may be important in deter- tive tissue abnormalities, hypercalcemia, and a distinctive mining the variable expressivity of 7q11.23 CNV pheno- neurobehavioral phenotype. Conversely, the phenotype of types. Here, we review the clinical and molecular Wndings patients carrying the 7q11.23 reciprocal duplications and the recent insights on genomic disorders associated includes less distinctive facial dysmorphisms and promi- with CNVs involving the 7q11.23 region. nent speech delay. The common deletion/duplication ranges in size from 1.5 to 1.8 Mb and encompasses approxi- mately 28 genes. This region is Xanked by low copy repeats Introduction (LCRs) with greater than »97% identity, which can medi- ate non-allelic homologous recombination resulting from Duplications and deletions, collectively known as copy misalignment of LCRs during meiosis. A clear genotype– number variants (CNVs), are the most prevalent types of phenotype correlation has been established in WBS only structural variations in the human genome (Iafrate et al. for the elastin gene, which is responsible for the vascular 2004; Redon et al. 2006; Sebat et al. 2004). Analysis of the and connective tissue abnormalities. The molecular sub- reference sequence shows that »5% of the human genome strates underlying the other clinical features of 7q11.23 contains CNVs (Bailey et al. 2002; McCarroll et al. 2008). While aVecting functions such as inXammatory response, immunity, and cell proliferation may play a key role in G. Merla (&) · L. Micale · C. Fusco human genome evolution, genomic duplications and dele- Laboratory of Medical Genetics, IRCCS Casa Sollievo Della tions are also an important cause of human diseases (Lupski V So erenza Hospital, San Giovanni Rotondo, Italy 1998) and disease susceptibility (Stankiewicz and Lupski e-mail: [email protected] 2002; Wain et al. 2009). Several studies found that CNVs N. Brunetti-Pierri make a substantial contribution to the genetic mechanisms Telethon Institute of Genetics and Medicine, underlying human diseases and provide greater insight into Via P. Castellino 111, Naples, Italy the etiology of phenotypes that result from complex genetic N. Brunetti-Pierri patterns of inheritance such as neurodevelopmental dis- Department of Pediatrics, eases, autism spectrum disorders, bipolar disorders, and Federico II University of Naples, Naples, Italy schizophrenia (Beckmann et al. 2007). CNVs result in the alteration of a variable number of genes causing changes in N. Brunetti-Pierri Department of Molecular and Human Genetics, gene dosages, which ultimately may lead to disease predis- Baylor College of Medicine, Houston, TX, USA position or speciWc clinical phenotypes. Moreover, as 123 4 Hum Genet (2010) 128:3–26 emerged more recently, the disruption of regulatory regions veriWed with the identiWcation of patients with 7q11.23 within the CNVs can also result into altered dosage and duplications (OMIM 609757). function of genes outside the deleted or duplicated intervals Given the frequency of patients with de novo microdele- (Henrichsen et al. 2009a; Henrichsen et al. 2009b; Merla tions of the WBS critical region, it is surprising that micro- et al. 2006). duplication of WBS region was Wrst reported only recently Chromosomal rearrangements below the limit of detec- (Somerville et al. 2005). This is likely due to a convergence tion of conventional karyotyping contribute signiWcantly to of factors. First, the phenotypes seen in patients with the cause of mental retardation and congenital malforma- 7q11.23 microduplications are quite unlike those seen with tions (Zhang et al. 2009). Interstitial deletions of 7q11.23 the common WBS microdeletion, and Xuorescent in situ cause Williams–Beuren syndrome (WBS; OMIM 194050), hybridization (FISH) analysis of metaphase cells is unlikely one of the best characterized genomic disorders aVecting 1/ to clearly detect the microduplication (ShaVer et al. 1997). 7,500–1/10,000 live births (Stromme et al. 2002). As with Clinicians were unlikely to order interphase FISH for WBS many other genomic disorders, the common recurrent 1.55- in patients who were not clinically suspected to have WBS. Mb microdeletion occurs by non-allelic homologous In fact, the Wrst patient reported to harbor a microduplica- recombination (NAHR) (Stankiewicz and Lupski 2002) tion of chromosome 7q11.23 was initially evaluated for between LCRs (Urban et al. 1996) Xanking the deleted velocardiofacial syndrome (VCFS) by real-time quantita- region (Bayes et al. 2003; Hillier et al. 2003) (Fig. 1). tive PCR (qPCR) that instead fortuitously revealed duplica- Because NAHR can generate both microdeletions and tion of markers within the WBS region (Somerville et al. microduplications, it was suspected that reciprocal micro- 2005). Second, although the recombination reciprocal of duplication of microdeletion syndromes should also occur the WBS microdeletion was postulated to occur (Lupski (Lupski 1998). With the advent of diagnostic array compar- 1998), it would have been diYcult to predict the phenotype ative genomic hybridization (aCGH), this prediction was associated with the microduplication based on what was Fig. 1 Schematic representation of 7q11.23 genomic rearrangements medial copy of LCR block B and within the centromeric and the medial (not drawn to scale). The centromeric (c), middle (m), and telomeric (t) copy of LCR block A are shown. Schematic representation of the LCRs are shown as colored arrows with their relative orientation to 7q11.23 deletion, duplication, triplication, and inversion are shown. In each other. Please note that multicopy genes within the blocks are the triplication case, the location of the breakpoints is shown with represented only once. In the middle, the common deletions of 1.5 and black dots representing the blocks Am, Bt and the region between 1.8 Mb are depicted; breakpoints within the centromeric and the FZD9 and BAZ1B genes, respectively 123 Hum Genet (2010) 128:3–26 5 known about the contributions of genes in this region to the speciWc growth charts is recommended (Giannotti et al. WBS phenotype. 2001; Hill et al. 2005; Pittschieler et al. 1993; Partsch et al. 1999; Santer et al. 1996). Although it was recognized early as a feature of WBS 7q11.23 deletion syndrome: clinical Wndings (Black and Carter 1963), transient hypercalcemia is docu- mented only in a minority (6–15%) of patients (American The Wrst pictures of patients with WBS were likely reported Academy of Pediatrics Committee on Genetics 2001; in 1956 by Dr. Schlesinger in a paper describing the associ- Amenta et al. 2005; Ferrero et al. 2007). ation of unusual facies and infantile hypercalcemia (Schle- A prevalence of 2–40% of hypothyroidism, which is singer et al. 1956). Dr. Williams was the Wrst to recognize more frequently subclinical, has been described (American WBS as a distinct clinical entity in 1961 (Williams et al. Academy of Pediatrics Committee on Genetics 2001; 1961) and shortly thereafter, Dr. Beuren reported four more Amenta et al. 2005; Cambiaso et al. 2007; Cherniske et al. WBS patients (Beuren et al. 1962). Since then the WBS 2004; Ferrero et al. 2007; Stagi et al. 2005). Reduced vol- phenotype has been extensively studied and aVected indi- ume and morphological abnormalities of the thyroid gland viduals typically have a distinctive facies, cardiovascular such as hypoplasia, hemiagenesis, and ectopia have been abnormalities, connective tissue anomalies, infantile hyper- reported (Cambiaso et al. 2007; Stagi et al. 2005). Another calcemia, and a characteristic neurocognitive and behav- common endocrine abnormality, especially in WBS adults, is ioral phenotype (Pober 2010). diabetes mellitus or impaired glucose tolerance (Cherniske et al. 2004). Facial characteristics Cardiovascular abnormalities and connective tissue The distinctive WBS facial Wndings include broad fore- involvement head, periorbital fullness, epicanthal folds, Xat nasal bridge, a short upturned nose, long philtrum, and wide mouth with The connective tissue abnormalities include a hoarse/deep full lips, full cheeks, and small jaw. In blue- and green-eyed voice, hernias, bladder/bowel diverticulae, soft/lax skin, individuals, a stellate or lacy pattern of the irides is usually joint laxity or limitation, and cardiovascular anomalies. The present (Greenberg and Lewis 1988). Patients with WBS spectrum, natural history, and pathological Wndings of car- also exhibit malocclusion, hypoplastic enamel, a high preva- diovascular and connective tissue lesions in WBS patients lence of dental caries, small and slender
Load more

Recommended publications
  • Analysis of Trans Esnps Infers Regulatory Network Architecture
    Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Anat Kreimer All rights reserved ABSTRACT Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer eSNPs are genetic variants associated with transcript expression levels. The characteristics of such variants highlight their importance and present a unique opportunity for studying gene regulation. eSNPs affect most genes and their cell type specificity can shed light on different processes that are activated in each cell. They can identify functional variants by connecting SNPs that are implicated in disease to a molecular mechanism. Examining eSNPs that are associated with distal genes can provide insights regarding the inference of regulatory networks but also presents challenges due to the high statistical burden of multiple testing. Such association studies allow: simultaneous investigation of many gene expression phenotypes without assuming any prior knowledge and identification of unknown regulators of gene expression while uncovering directionality. This thesis will focus on such distal eSNPs to map regulatory interactions between different loci and expose the architecture of the regulatory network defined by such interactions. We develop novel computational approaches and apply them to genetics-genomics data in human. We go beyond pairwise interactions to define network motifs, including regulatory modules and bi-fan structures, showing them to be prevalent in real data and exposing distinct attributes of such arrangements. We project eSNP associations onto a protein-protein interaction network to expose topological properties of eSNPs and their targets and highlight different modes of distal regulation.
    [Show full text]
  • Computational Genome-Wide Identification of Heat Shock Protein Genes in the Bovine Genome [Version 1; Peer Review: 2 Approved, 1 Approved with Reservations]
    F1000Research 2018, 7:1504 Last updated: 08 AUG 2021 RESEARCH ARTICLE Computational genome-wide identification of heat shock protein genes in the bovine genome [version 1; peer review: 2 approved, 1 approved with reservations] Oyeyemi O. Ajayi1,2, Sunday O. Peters3, Marcos De Donato2,4, Sunday O. Sowande5, Fidalis D.N. Mujibi6, Olanrewaju B. Morenikeji2,7, Bolaji N. Thomas 8, Matthew A. Adeleke 9, Ikhide G. Imumorin2,10,11 1Department of Animal Breeding and Genetics, Federal University of Agriculture, Abeokuta, Nigeria 2International Programs, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, 14853, USA 3Department of Animal Science, Berry College, Mount Berry, GA, 30149, USA 4Departamento Regional de Bioingenierias, Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Queretaro, Mexico 5Department of Animal Production and Health, Federal University of Agriculture, Abeokuta, Nigeria 6Usomi Limited, Nairobi, Kenya 7Department of Animal Production and Health, Federal University of Technology, Akure, Nigeria 8Department of Biomedical Sciences, Rochester Institute of Technology, Rochester, NY, 14623, USA 9School of Life Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa 10School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30032, USA 11African Institute of Bioscience Research and Training, Ibadan, Nigeria v1 First published: 20 Sep 2018, 7:1504 Open Peer Review https://doi.org/10.12688/f1000research.16058.1 Latest published: 20 Sep 2018, 7:1504 https://doi.org/10.12688/f1000research.16058.1 Reviewer Status Invited Reviewers Abstract Background: Heat shock proteins (HSPs) are molecular chaperones 1 2 3 known to bind and sequester client proteins under stress. Methods: To identify and better understand some of these proteins, version 1 we carried out a computational genome-wide survey of the bovine 20 Sep 2018 report report report genome.
    [Show full text]
  • RFC2 Antibody
    Product Datasheet RFC2 Antibody Catalog No: #43122 Orders: [email protected] Description Support: [email protected] Product Name RFC2 Antibody Host Species Rabbit Clonality Polyclonal Purification Antigen affinity purification. Applications WB Species Reactivity Hu Specificity The antibody detects endogenous levels of total RFC2 protein. Immunogen Type peptide Immunogen Description Synthetic peptide of human RFC2 Target Name RFC2 Other Names RFC40 Accession No. Swiss-Prot#: P35250Gene ID: 5982 Calculated MW 39kd Concentration 3.5mg/ml Formulation Rabbit IgG in pH7.4 PBS, 0.05% NaN3, 40% Glycerol. Storage Store at -20°C Application Details Western blotting: 1:200-1:1000 Immunohistochemistry: 1:30-1:150 Images Gel: 10%SDS-PAGE Lysate: 40 µg Lane: Human liver cancer tissue Primary antibody: 1/500 dilution Secondary antibody: Goat anti rabbit IgG at 1/8000 dilution Exposure time: 20 seconds Background This gene encodes a member of the activator 1 small subunits family. The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins, proliferating cell nuclear antigen (PCNA) and replication factor C (RFC). Replication factor C, also called activator 1, is a protein complex consisting of five distinct subunits. This gene encodes the 40 kD subunit, which has been shown to be responsible for binding ATP and may help promote cell survival. Disruption of this gene is associated with Williams syndrome. Alternatively spliced transcript variants Address: 8400 Baltimore Ave., Suite 302, College Park, MD 20740, USA http://www.sabbiotech.com 1 encoding distinct isoforms have been described. A pseudogene of this gene has been defined on chromosome 2.
    [Show full text]
  • Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-Like Mouse Models: Tracking the Role of the Hairless Gene
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 5-2006 Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene Yutao Liu University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Liu, Yutao, "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino- like Mouse Models: Tracking the Role of the Hairless Gene. " PhD diss., University of Tennessee, 2006. https://trace.tennessee.edu/utk_graddiss/1824 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Yutao Liu entitled "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Life Sciences. Brynn H. Voy, Major Professor We have read this dissertation and recommend its acceptance: Naima Moustaid-Moussa, Yisong Wang, Rogert Hettich Accepted for the Council: Carolyn R.
    [Show full text]
  • Program Nr: 1 from the 2004 ASHG Annual Meeting Mutations in A
    Program Nr: 1 from the 2004 ASHG Annual Meeting Mutations in a novel member of the chromodomain gene family cause CHARGE syndrome. L.E.L.M. Vissers1, C.M.A. van Ravenswaaij1, R. Admiraal2, J.A. Hurst3, B.B.A. de Vries1, I.M. Janssen1, W.A. van der Vliet1, E.H.L.P.G. Huys1, P.J. de Jong4, B.C.J. Hamel1, E.F.P.M. Schoenmakers1, H.G. Brunner1, A. Geurts van Kessel1, J.A. Veltman1. 1) Dept Human Genetics, UMC Nijmegen, Nijmegen, Netherlands; 2) Dept Otorhinolaryngology, UMC Nijmegen, Nijmegen, Netherlands; 3) Dept Clinical Genetics, The Churchill Hospital, Oxford, United Kingdom; 4) Children's Hospital Oakland Research Institute, BACPAC Resources, Oakland, CA. CHARGE association denotes the non-random occurrence of ocular coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies and deafness (OMIM #214800). Almost all patients with CHARGE association are sporadic and its cause was unknown. We and others hypothesized that CHARGE association is due to a genomic microdeletion or to a mutation in a gene affecting early embryonic development. In this study array- based comparative genomic hybridization (array CGH) was used to screen patients with CHARGE association for submicroscopic DNA copy number alterations. De novo overlapping microdeletions in 8q12 were identified in two patients on a genome-wide 1 Mb resolution BAC array. A 2.3 Mb region of deletion overlap was defined using a tiling resolution chromosome 8 microarray. Sequence analysis of genes residing within this critical region revealed mutations in the CHD7 gene in 10 of the 17 CHARGE patients without microdeletions, including 7 heterozygous stop-codon mutations.
    [Show full text]
  • RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases
    G C A T T A C G G C A T genes Review RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases Amber Willbanks, Shaun Wood and Jason X. Cheng * Department of Pathology, Hematopathology Section, University of Chicago, Chicago, IL 60637, USA; [email protected] (A.W.); [email protected] (S.W.) * Correspondence: [email protected] Abstract: Chromatin structure plays an essential role in eukaryotic gene expression and cell identity. Traditionally, DNA and histone modifications have been the focus of chromatin regulation; however, recent molecular and imaging studies have revealed an intimate connection between RNA epigenetics and chromatin structure. Accumulating evidence suggests that RNA serves as the interplay between chromatin and the transcription and splicing machineries within the cell. Additionally, epigenetic modifications of nascent RNAs fine-tune these interactions to regulate gene expression at the co- and post-transcriptional levels in normal cell development and human diseases. This review will provide an overview of recent advances in the emerging field of RNA epigenetics, specifically the role of RNA modifications and RNA modifying proteins in chromatin remodeling, transcription activation and RNA processing, as well as translational implications in human diseases. Keywords: 5’ cap (5’ cap); 7-methylguanosine (m7G); R-loops; N6-methyladenosine (m6A); RNA editing; A-to-I; C-to-U; 2’-O-methylation (Nm); 5-methylcytosine (m5C); NOL1/NOP2/sun domain Citation: Willbanks, A.; Wood, S.; (NSUN); MYC Cheng, J.X. RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases. Genes 2021, 12, 627.
    [Show full text]
  • Gene Expression Is Related to Parental Origin and Regional Coordinate Control
    Journal of Human Genetics (2009) 54, 193–198 & 2009 The Japan Society of Human Genetics All rights reserved 1434-5161/09 $32.00 www.nature.com/jhg ORIGINAL ARTICLE William’s syndrome: gene expression is related to parental origin and regional coordinate control Jeremy C Collette1, Xiao-Ning Chen1, Debra L Mills2, Albert M Galaburda3, Allan L Reiss4, Ursula Bellugi5 and Julie R Korenberg1,6 William’s syndrome (WS) features a spectrum of neurocognitive and behavioral abnormalities due to a rare 1.5 MB deletion that includes about 24–28 genes on chromosome band 7q11.23. Study of the expression of these genes from the single normal copy provides an opportunity to elucidate the genetic and epigenetic controls on these genes as well as their roles in both WS and normal brain development and function. We used quantitative RT-PCR to determine the transcriptional level of 14 WS gene markers in a cohort of 77 persons with WS and 48 normal controls. Results reported here: (1) show that the expression of the genes deleted in WS is decreased in some but not all cases, (2) demonstrate that the parental origin of the deletion contributes to the level of expression of GTF2I independently of age and gender and (3) indicate that the correlation of expression between GTF2I and some other genes in the WS region differs in WS subjects and normal controls, which in turn points toward a regulatory role for this gene. Interspecies comparisons suggest GTF2I may play a key role in normal brain development. Journal of Human Genetics (2009) 54, 193–198; doi:10.1038/jhg.2009.5; published online 13 March 2009 Keywords: William’s syndrome; gene expression; RT-PCR; parental origin; GTF2I INTRODUCTION As an approach toward understanding the role of the deleted genes William’s syndrome (WS) is a neurogenetic disorder affecting human in WS, we have characterized WS subjects according to genetic, social/ development and adult cognition.
    [Show full text]
  • Williams Syndrome Specialized Health Needs Interagency Collaboration
    SHNIC Factsheet: Williams Syndrome Specialized Health Needs Interagency Collaboration What is it? Williams syndrome (WS) is a random genetic mutation disorder that presents at birth, affecting both boys and girls equally. WS is caused by the deletion of genetic material from a specific region of chromosome 7. This disease is characterized by an array of medical problems that can range in severity and age of onset. However, all cases are characterized by dysmorphic facial features, cardiovascular disease, and developmental delay. These disabilities occur in conjunction with striking verbal abilities, highly social personalities, and an affinity for music. What are characteristics? Heart and blood vessel problems Low muscle tone and joint laxity Reflux Dental abnormalities Hypercalcemia Developmental Delays Hearing sensitivity Characteristic facial features: Kidney problems small upturned nose Hernias wide mouth Facial characteristics full lips Chronic ear infection small chin puffiness around the eyes Suggested school accommodations Most children with Williams Syndrome have some form of learning difficulties but they can significant- ly vary. As they age, you may notice the child struggling with concepts like spatial relations, numbers and abstract reasoning. Many children with WS appear scattered in their level of abilities across do- mains. Although a child with WS may be very social, remember to monitor their support systems and social interactions as they often have a difficult time understanding social cues. Physical/Medical
    [Show full text]
  • Structure of the Human Clamp Loader Reveals an Autoinhibited Conformation of a Substrate-Bound AAA+ Switch
    Structure of the human clamp loader reveals an autoinhibited conformation of a substrate-bound AAA+ switch Christl Gaubitza,1, Xingchen Liua,b,1, Joseph Magrinoa,b, Nicholas P. Stonea, Jacob Landecka,b, Mark Hedglinc, and Brian A. Kelcha,2 aDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester MA 01605; bGraduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester MA 01605; and cDepartment of Chemistry, The Pennsylvania State University, University Park, PA 16802 Edited by Michael E. O’Donnell, HHMI and Rockefeller University, New York, NY, and approved July 27, 2020 (received for review April 20, 2020) DNA replication requires the sliding clamp, a ring-shaped protein areflexia syndrome (15), Hutchinson–Gilford progeria syn- complex that encircles DNA, where it acts as an essential cofactor drome (16), and in the replication of some viruses (17–19). It for DNA polymerases and other proteins. The sliding clamp needs is unknown whether loading by RFC contributes to PARD to be opened and installed onto DNA by a clamp loader ATPase of disease. the AAA+ family. The human clamp loader replication factor C Clamp loaders are members of the AAA+ family of ATPases (RFC) and sliding clamp proliferating cell nuclear antigen (PCNA) (ATPases associated with various cellular activities), a large are both essential and play critical roles in several diseases. De- protein family that uses the chemical energy of adenosine 5′- spite decades of study, no structure of human RFC has been re- triphosphate (ATP) to generate mechanical force (20). Most solved. Here, we report the structure of human RFC bound to AAA+ proteins form hexameric motors that use an undulating PCNA by cryogenic electron microscopy to an overall resolution ∼ spiral staircase mechanism to processively translocate a substrate of 3.4 Å.
    [Show full text]
  • The Nuclear Localization Pattern and Interaction Partners of GTF2IRD1 Demonstrate a Role in Chromatin Regulation
    Hum Genet DOI 10.1007/s00439-015-1591-0 ORIGINAL INVESTIGATION The nuclear localization pattern and interaction partners of GTF2IRD1 demonstrate a role in chromatin regulation Paulina Carmona‑Mora1 · Jocelyn Widagdo2 · Florence Tomasetig1 · Cesar P. Canales1 · Yeojoon Cha1 · Wei Lee1 · Abdullah Alshawaf3 · Mirella Dottori3 · Renee M. Whan4 · Edna C. Hardeman1 · Stephen J. Palmer1 Received: 11 February 2015 / Accepted: 4 August 2015 © Springer-Verlag Berlin Heidelberg 2015 Abstract GTF2IRD1 is one of the three members of the mostly involved in chromatin modification and transcrip- GTF2I gene family, clustered on chromosome 7 within a tional regulation, whilst others indicate an unexpected role 1.8 Mb region that is prone to duplications and deletions in connection with the primary cilium. Mapping of the sites in humans. Hemizygous deletions cause Williams–Beuren of protein interaction also indicates key features regarding syndrome (WBS) and duplications cause WBS duplica- the evolution of the GTF2IRD1 protein. These data provide tion syndrome. These copy number variations disturb a a visual and molecular basis for GTF2IRD1 nuclear func- variety of developmental systems and neurological func- tion that will lead to an understanding of its role in brain, tions. Human mapping data and analyses of knockout mice behaviour and human disease. show that GTF2IRD1 and GTF2I underpin the craniofacial abnormalities, mental retardation, visuospatial deficits and Abbreviations hypersociability of WBS. However, the cellular role of the hESC Human embryonic stem cells GTF2IRD1 protein is poorly understood due to its very PLA Proximity ligation assay low abundance and a paucity of reagents. Here, for the first STED Stimulated emission depletion time, we show that endogenous GTF2IRD1 has a punctate WBS Williams–Beuren syndrome pattern in the nuclei of cultured human cell lines and neu- Y2H Yeast two-hybrid rons.
    [Show full text]
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement.
    [Show full text]
  • The Contribution of CLIP2 Haploinsufficiency to the Clinical
    REPORT The Contribution of CLIP2 Haploinsufficiency to the Clinical Manifestations of the Williams-Beuren Syndrome Geert Vandeweyer,1 Nathalie Van der Aa,1 Edwin Reyniers,1 and R. Frank Kooy1,* Williams-Beuren syndrome is a rare contiguous gene syndrome, characterized by intellectual disability, facial dysmorphisms, connec- tive-tissue abnormalities, cardiac defects, structural brain abnormalities, and transient infantile hypercalcemia. Genes lying telomeric to RFC2, including CLIP2, GTF2I and GTF2IRD1, are currently thought to be the most likely major contributors to the typical Williams syndrome cognitive profile, characterized by a better-than-expected auditory rote-memory ability, a relative sparing of language capa- bilities, and a severe visual-spatial constructive impairment. Atypical deletions in the region have helped to establish genotype-pheno- type correlations. So far, however, hardly any deletions affecting only a single gene in the disease region have been described. We present here two healthy siblings with a pure, hemizygous deletion of CLIP2. A putative role in the cognitive and behavioral abnormalities seen in Williams-Beuren patients has been suggested for this gene on the basis of observations in a knock-out mouse model. The presented siblings did not show any of the clinical features associated with the syndrome. Cognitive testing showed an average IQ for both and no indication of the Williams syndrome cognitive profile. This shows that CLIP2 haploinsufficiency by itself does not lead to the physical or cognitive characteristics of the Williams-Beuren syndrome, nor does it lead to the Williams syndrome cognitive profile. Although contri- bution of CLIP2 to the phenotype cannot be excluded when it is deleted in combination with other genes, our results support the hypothesis that GTF2IRD1 and GTF2I are the main genes causing the cognitive defects associated with Williams-Beuren syndrome.
    [Show full text]