DOCSLIB.ORG

Microcephaly Genes and Risk of Late-Onset Alzheimer Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Microcephaly Genes and Risk of Late-Onset Alzheimer Disease ORIGINAL ARTICLE Microcephaly Genes and Risk of Late-onset Alzheimer Disease Deniz Erten-Lyons, MD,*w Beth Wilmot, PhD,zy Pavana Anur, BS,z Shannon McWeeney, PhD,zyJ Shawn K. Westaway, PhD,w Lisa Silbert, MD,w Patricia Kramer, PhD,w and Jeffrey Kaye, MD*w Alzheimer’s Disease Neuroimaging Initiative ratio=3.41; confidence interval, 1.77-6.57). However, this associa- Abstract: Brain development in the early stages of life has been tion was not replicated using another case-control sample research suggested to be one of the factors that may influence an individual’s participants from the Alzheimer Disease Neuroimaging Initiative. risk of Alzheimer disease (AD) later in life. Four microcephaly We conclude that the common variations we measured in the 4 genes, which regulate brain development in utero and have been microcephaly genes do not affect the risk of AD or that their effect suggested to play a role in the evolution of the human brain, were size is small. selected as candidate genes that may modulate the risk of AD. We examined the association between single nucleotide polymorphisms Key Words: Alzheimer disease, microcephaly genes, cognitive tagging common sequence variations in these genes and risk of AD reserve in two case-control samples. We found that the G allele of (Alzheimer Dis Assoc Disord 2011;25:276–282) rs2442607 in microcephalin 1 was associated with an increased risk of AD (under an additive genetic model, P=0.01; odds Received for publication June 2, 2010; accepted December 2, 2010. enetics has been suggested to play a role in variations From the *Portland Veterans Affairs Medical Center; wDepartment of Gin cognitive function in late life.1 One way in which Neurology; zOregon Clinical and Translational Research Center; genes may play a role in cognitive function in late life is yDivision of Bioinformatics and Computational Biology, Depart- through providing an “initial endowment” that is more ment of Medical Informatics and Clinical Epidemiology; and JDivision of Biostatistics, Department of Public Health and resistant to age-related changes. This initial endowment, or Preventative Medicine, Oregon Health and Science University, cognitive reserve, may include both functional and struc- Portland, OR. tural brain features (such as cerebral size), which may Supported by Merit Review Grant and Research Career Development increase the threshold for responses to brain insult.2 We Award, Office of Research and Development, Department of Veterans Affairs, National Institutes of Health (AG08017, MO1 hypothesize that variations in genes regulating brain size RR000334, UL1 RR024140), Alzheimer Tax Check-off Grant. during neurodevelopment may play a role in individual Data collection and sharing for this project was funded by the susceptibility to cognitive decline by modulating the brain Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National size. This study examines whether 4 microcephaly genes Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical (abnormal spindle-like microcephaly-associated (ASPM)), Imaging and Bioengineering, and through generous contributions microcephalin 1 (MCPH1), centromeric protein J (CENPJ), from the following: Abbott; AstraZeneca AB; Bayer Schering and cyclin-dependent kinase 5 regulatory subunit-asso- Pharma AG; Bristol-Myers Squibb; Eisai Global Clinical Devel- ciated protein 2 (CDK5RAP2)) play a role in late-life risk of opment; Elan Corporation; Genentech; GE Healthcare; GlaxoS- mithKline; Innogenetics; Johnson and Johnson; Eli Lilly and Co.; Alzheimer disease (AD). Medpace, Inc.; Merck and Co., Inc.; Novartis AG; Pfizer Inc.; F. Mutations in these 4 genes cause reduced brain size Hoffman-La Roche; Schering-Plough; Synarc, Inc.; and nonprofit and head circumference and mental retardation.3 The partners the Alzheimer’s Association and Alzheimer’s Drug microcephaly genes are expressed in the embryonic brain, Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are especially in the ventricular zone, during cerebral cortical facilitated by the Foundation for the National Institutes of Health neurogenesis.4 The timing and location of their expres- (www.fnih.org). The grantee organization is the Northern Califor- sion suggest that they play a role in regulating neurogenic nia Institute for Research and Education, and the study is mitosis before birth.4 Sequence comparisons among pri- coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated mate species suggest that microcephaly genes experienced by the Laboratory for Neuro Imaging at the University of adaptive evolution due to positive selection5–9; rare variants California, Los Angeles. This research was also supported by in these genes increased in frequency over time due to an NIH grants P30 AG010129, K01 AG030514, and the Dana advantageous phenotype they provide. Foundation. The Alzheimer’s Disease Neuroimaging Initiative: Data used in the There is also evidence that 2 haplotype-defining single preparation of this article were obtained from the ADNI database nucleotide polymorphisms (SNPs) in ASPM and MCPH1, (www.loni.ucla.edu/ADNI). As such, the investigators within the rs41310927 and rs930557, respectively, have continued to ADNI contributed to the design and implementation of ADNI and/ work under positive selection, beyond the emergence of the or provided data but did not participate in the analysis or the 6–8 writing of this report. Complete listing of ADNI investigators anatomically modern humans. Earlier studies imply that is available at: www.loni.ucla.edu\ADNI\Collaboration\ADNI\ the positive selection in the microcephaly genes may be Manuscript\Citations.pdf related to an advantageous brain-associated phenotype, Reprints: Deniz Erten-Lyons, MD, National Institute of Aging, Layton such as brain size, cognition, personality, motor control, or Aging and Alzheimer’s Disease Center, 3181 SW Sam Jackson Park Road CR 131, Portland, OR 97239 (e-mail: [email protected]). susceptibility to neurological or psychiatric disease. Several Copyright r 2011 by Lippincott Williams & Wilkins studies have specifically investigated a relationship between 276 | www.alzheimerjournal.com Alzheimer Dis Assoc Disord Volume 25, Number 3, July–September 2011 Alzheimer Dis Assoc Disord Volume 25, Number 3, July–September 2011 Microcephaly Genes and Risk of Late-onset AD such phenotypes and some or all of the microcephaly (4) had no first-degree family history of AD (to ensure that genes.10–16 Most of the studies to date have found no none of the participants had an undescribed genetic association between brain-related phenotypes (brain vo- predilection for AD that could confound the analyses); lumes, general cognitive ability, head circumference, or risk and (5) were either >69 years old (for the first discovery of schizophrenia) and these 2 polymorphisms. Only 2 case-control sample) or were >64 years old (for the second studies have found associations between common SNPs in discovery case-control sample) at the onset of symptoms MCPH1, CDK5RAP2, or ASPM and brain volumes in a for cases or at the last evaluation for controls. When sex-specific manner.13,16 One of these studies also sought comparing basic demographics between cohorts to ensure for an association between 2 SNPs in CDK5RAP2 and that cohort differences were not confounding the analysis, it schizophrenia, bipolar spectrum disorder, AD, and mild became evident that participants from the memory clinic cognitive impairment (MCI) and found no association.16 were younger than the participants in the longitudinal aging In this study, we examined the association between the studies. Therefore, an age criteria was added. This criteria microcephaly genes and risk of AD using tag SNPs was reduced to >64 years in the second case-control sample covering all 4 genes. To test our hypothesis, we completed to increase the sample size. Those with a CDR of 0.5 and not a 2-step study. In the discovery step, 2 related but separate meeting diagnostic criteria for AD were excluded. case-control studies were carried out: first the association between SNPs in ASPM and AD risk was examined. SNP Selection and Genotyping Later, the association between MCPH1, CDK5RAP2, and A tag SNP panel was generated using data obtained CENPJ SNPs and AD risk was examined in a slightly from a pilot study24 and the HapMap CEU (Utah larger case-control sample. Data from the Alzheimer’s Residents with Northern and Western European Ancestry) Disease Neuroimaging Initiative (ADNI) were used to population.25 In the pilot study, coding regions of ASPM validate the findings from the discovery step. were resequenced in an independent sample of 59 partici- pants (30 cases and 29 controls) from our study population. METHODS We determined that the frequencies of the ASPM SNPs in The Portland Veterans Affairs Medical Center Institu- our population were comparable with the HapMap CEU tional Review Board approved this study. population. Therefore, tag SNPs spanning the entire ASPM gene were selected using Haploview 3.2 based on data Description of Participants obtained from the HapMap CEU population. Haploview 26 Participants were selected from longitudinal aging uses a method that is identical to the program Tagger. A studies conducted at the Oregon Alzheimer Disease Center pair-wise tagging method using single markers with thresh- 2 (OADC). These
Load more

Recommended publications
  • Epigenetic Control of Mammalian Centromere Protein Binding: Does DNA Methylation Have a Role?
    Journal of Cell Science 109, 2199-2206 (1996) 2199 Printed in Great Britain © The Company of Biologists Limited 1996 JCS3386 Epigenetic control of mammalian centromere protein binding: does DNA methylation have a role? Arthur R. Mitchell*, Peter Jeppesen, Linda Nicol†, Harris Morrison and David Kipling MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK *Author for correspondence (internet [email protected]) †Present address: MRC Reproductive Biology Unit, Edinburgh, UK SUMMARY Chromosome 1 of the inbred mouse strain DBA/2 has a block of minor satellite DNA sequences on chromosome 1. polymorphism associated with the minor satellite DNA at The binding of the CENP-E protein does not appear to be its centromere. The more terminal block of satellite DNA affected by demethylation of the minor satellite sequences. sequences on this chromosome acts as the centromere as We present a model to explain these observations. This shown by the binding of CREST ACA serum, anti-CENP- model may also indicate the mechanism by which the B and anti-CENP-E polyclonal sera. Demethylation of the CENP-B protein recognises specific sites within the arrays minor satellite DNA sequences accomplished by growing of minor satellite DNA on mouse chromosomes. cells in the presence of the drug 5-aza-2′-deoxycytidine results in a redistribution of the CENP-B protein. This protein now binds to an enlarged area on the more terminal Key words: Centromere satellite DNA, Demethylation, Centromere block and in addition it now binds to the more internal antibody INTRODUCTION A common feature of many mammalian pericentromeric domains is that they contain families of repetitive DNA The centromere of mammalian chromosomes is recognised at sequences (Singer, 1982).
    [Show full text]
  • The University of Chicago Genetic Services Laboratories Genetic
    The University of Chicago Genetic Services Laboratories 5841 S. Maryland Ave., Rm. G701, MC 0077, Chicago, Illinois 60637 Toll Free: (888) UC GENES (888) 824 3637 Local: (773) 834 0555 FAX: (312) 729 2808 [email protected] dnatesting.uchicago.edu CLIA #: 14D0917593 CAP #: 18827-49 Genetic Testing for Primary Microcephaly Autosomal recessive primary microcephaly (MCPH): • Congenital microcephaly (3 SD below the mean at birth or at least 4 SD below the mean at later ages) • Mental retardation (MR), but no other neurological findings (febrile or other mild seizures do not exclude the diagnosis) • Normal or mildly short stature that is less severe than the markedly small head circumference • Normal weight and appearance except for the microcephaly Brain imaging shows a mildly reduced number of gyri, and in some patients may also demonstrate agenesis of the corpus callosum or a few periventricular nodular heterotopia (numerous heterotopia suggest an alternative diagnosis). Prenatally, individuals have normal head size until approximately 20 weeks and decreased head size by 32 weeks, although this varies. The relative degree of microcephaly doesn’t vary throughout life and doesn’t vary within a family by more than 2 SD. MR is usually mild to moderate with no progressive decline or motor deficit [1]. Mutations in the ASPM [OMIM #605481] gene are the most common cause of MCPH [2]. Approximately 40% of patients (both consanguineous and non-consanguineous) with a strict diagnosis of MCPH have mutations in ASPM. However, very few patients (<10%) with a less restrictive phenotype have mutations in ASPM [3]. Thus, we expect a high detection rate for high-functioning MCPH, but a lower detection rate for low-functioning MCPH, especially if associated with other anomalies.
    [Show full text]
  • Congenital Microcephaly
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Sussex Research Online American Journal of Medical Genetics Part C (Seminars in Medical Genetics) ARTICLE Congenital Microcephaly DIANA ALCANTARA AND MARK O'DRISCOLL* The underlying etiologies of genetic congenital microcephaly are complex and multifactorial. Recently, with the exponential growth in the identification and characterization of novel genetic causes of congenital microcephaly, there has been a consolidation and emergence of certain themes concerning underlying pathomechanisms. These include abnormal mitotic microtubule spindle structure, numerical and structural abnormalities of the centrosome, altered cilia function, impaired DNA repair, DNA Damage Response signaling and DNA replication, along with attenuated cell cycle checkpoint proficiency. Many of these processes are highly interconnected. Interestingly, a defect in a gene whose encoded protein has a canonical function in one of these processes can often have multiple impacts at the cellular level involving several of these pathways. Here, we overview the key pathomechanistic themes underlying profound congenital microcephaly, and emphasize their interconnected nature. © 2014 Wiley Periodicals, Inc. KEY WORDS: cell division; mitosis; DNA replication; cilia How to cite this article: Alcantara D, O'Driscoll M. 2014. Congenital microcephaly. Am J Med Genet Part C Semin Med Genet 9999:1–16. INTRODUCTION mid‐gestation although glial cell division formation of the various cortical layers. and consequent brain volume enlarge- Furthermore, differentiating and devel- Congenital microcephaly, an occipital‐ ment does continue after birth [Spalding oping neurons must migrate to their frontal circumference of equal to or less et al., 2005]. Impaired neurogenesis is defined locations to construct the com- than 2–3 standard deviations below the therefore most obviously reflected clini- plex architecture and laminar layered age‐related population mean, denotes cally as congenital microcephaly.
    [Show full text]
  • Identification and Characterization of Genes Essential for Human Brain Development
    Identification and Characterization of Genes Essential for Human Brain Development The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Ganesh, Vijay S. 2012. Identification and Characterization of Genes Essential for Human Brain Development. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:9773743 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Copyright © 2012 by Vijay S. Ganesh All rights reserved. Dissertation Advisor: Dr. Christopher A. Walsh Author: Vijay S. Ganesh Identification and Characterization of Genes Essential for Human Brain Development Abstract The human brain is a network of ninety billion neurons that allows for many of the behavioral adaptations considered unique to our species. One-fifth of these neurons are layered in an epithelial sheet known as the cerebral cortex, which is exquisitely folded into convolutions called gyri. Defects in neuronal number clinically present with microcephaly (Greek for “small head”), and in inherited cases these defects can be linked to mutations that identify genes essential for neural progenitor proliferation. Most microcephaly genes are characterized to play a role in the centrosome, however rarer presentations of microcephaly have identified different mechanisms. Charged multivesicular body protein/Chromatin modifying protein 1A (CHMP1A) is a member of the ESCRT-III endosomal sorting complex, but is also suggested to localize to the nuclear matrix and regulate chromatin.
    [Show full text]
  • A Nonsense (C.3978G>A) Abnormal Spindle-Like, Microcephaly Associated (ASPM) Gene Mutation Is a Major Cause of Primary Microc
    African Journal of Biotechnology Vol. 10(34), pp. 6396-6400, 11 July, 2011 Available online at http://www.academicjournals.org/AJB DOI: 10.5897/AJB10.2571 ISSN 1684-5315 © 2011 Academic Journals Full Length Research Paper A nonsense (c.3978G>A) abnormal spindle-like, microcephaly associated (ASPM) gene mutation is a major cause of primary microcephaly in Pashtoon ethnic group of Pakistan Shamim Saleha 1, Muhammad Ajmal 2, Muhammad Jamil 1, Muhammad Nasir 2 and Abdul Hameed 2* 1Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology, Kohat 26000, Khyber Paktoonkhwa, Pakistan. 2Institute of Biomedical and Genetic Engineering, G.P.O. box 2891, 24-Mauve Area, G-9/1, Islamabad, Pakistan. Accepted 29 April, 2011 Primary microcephaly (MCPH) is an autosomal-recessive congenital disorder characterized by smaller- than-normal brain size and mental retardation. MCPH is genetically heterogeneous with six known loci: MCPH1 to MCPH7. The abnormal spindle-like, microcephaly associated (ASPM) gene at MCPH5 locus, which accounts for 37 to 54% of MCPH, appears to be the most common cause of microcephaly. More than 50% of the MCPH families genetically analyzed in Pakistan were mapped to MCPH5 locus including both families in this study. On mutation screening of ASPM gene by PCR amplification and direct DNA sequencing, a common c.3978G>A transition was identified in exon 17 of ASPM gene to be responsible for diseased phenotype in both families. This change results to the substitution of an amino acid residue at position 1326 from tryptophan to a stop codon (p.Trp1326Stop). The same mutation was also identified in several other families of Pakistani origin.
    [Show full text]
  • Molecular Genetics of Microcephaly Primary Hereditary: an Overview
    brain sciences Review Molecular Genetics of Microcephaly Primary Hereditary: An Overview Nikistratos Siskos † , Electra Stylianopoulou †, Georgios Skavdis and Maria E. Grigoriou * Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece; [email protected] (N.S.); [email protected] (E.S.); [email protected] (G.S.) * Correspondence: [email protected] † Equal contribution. Abstract: MicroCephaly Primary Hereditary (MCPH) is a rare congenital neurodevelopmental disorder characterized by a significant reduction of the occipitofrontal head circumference and mild to moderate mental disability. Patients have small brains, though with overall normal architecture; therefore, studying MCPH can reveal not only the pathological mechanisms leading to this condition, but also the mechanisms operating during normal development. MCPH is genetically heterogeneous, with 27 genes listed so far in the Online Mendelian Inheritance in Man (OMIM) database. In this review, we discuss the role of MCPH proteins and delineate the molecular mechanisms and common pathways in which they participate. Keywords: microcephaly; MCPH; MCPH1–MCPH27; molecular genetics; cell cycle 1. Introduction Citation: Siskos, N.; Stylianopoulou, Microcephaly, from the Greek word µικρoκεϕαλi´α (mikrokephalia), meaning small E.; Skavdis, G.; Grigoriou, M.E. head, is a term used to describe a cranium with reduction of the occipitofrontal head circum- Molecular Genetics of Microcephaly ference equal, or more that teo standard deviations
    [Show full text]
  • Numerical Chromosome 1, 7, 9, and 11 Aberrations in Bladder Cancer Detected by in Situ Hybridization1
    [CANCER RESEARCH 51, 644-651, January 15. 1991] Numerical Chromosome 1, 7, 9, and 11 Aberrations in Bladder Cancer Detected by in Situ Hybridization1 Anton H. N. Hopman,2 Olof Moesker, A. Wim G. B. Smeets, Ruud P. E. Pauwels, G. Peter Vooijs, and Frans C. S. Ramaekers Department of Pathology, L'niversity //ospitai Nijmegen, fieert Grooteplein Zulu 24, 6525 (iA, .\ijmegen ¡A.H. N. H., O. .\t., C. P. ('./.' Stickling Ziekenkuisapotkeek en Klinisch Laboratorium l'enray [A. H'. G. B. S.J; Department of Urology, Hospital I enlo-1 'enray [R. P. K. P.], and Department of Molecular Cell Biology, L'nirersity ofLimhurg, Maastricht ¡A.H. N. H., F. C. S. R.], The Netherlands. ABSTRACT studies we demonstrated that this approach enables a routine screening of large tumor cell populations in, for example, Forty transitional cell carcinomas of the human urinary bladder (TCCs) TCCs4 (5, 10). Furthermore, ISH enables the detection of minor were examined for numerical aberrations of chromosomes 1, 7, 9, and 11 by in situ hybridization using chromosome-specific probes. Our inter- cell populations or imbalance in chromosome copy number phase cytogenetic study of 24 low-grade, noninvasive TCCs, which were within one tumor. near-diploid by flow cytometry, showed a numerical aberration for at By means of conventional karyotyping nonrandom chromo least I of these chromosomes in 14 of these cases. Most strikingly, a some aberrations involving chromosomes 1, 7, 9, and 11 have monosomy for chromosome 9 was found in 9 of 24 low-grade TCCs. A been detected in bladder cancer.
    [Show full text]
  • Review Article Molecular and Cellular Basis of Autosomal Recessive Primary Microcephaly
    Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 547986, 13 pages http://dx.doi.org/10.1155/2014/547986 Review Article Molecular and Cellular Basis of Autosomal Recessive Primary Microcephaly Marine Barbelanne1,2 and William Y. Tsang1,2,3 1 Institut de Recherches Cliniques de Montreal,´ 110 avenue des Pins Ouest, Montreal,QC,CanadaH2W1R7´ 2 FacultedeM´ edecine,´ UniversitedeMontr´ eal,´ Montreal,QC,CanadaH3C3J7´ 3 Division of Experimental Medicine, McGill University, Montreal,´ QC, Canada H3A 1A3 Correspondence should be addressed to William Y. Tsang; [email protected] Received 16 July 2014; Revised 18 September 2014; Accepted 18 September 2014; Published 8 December 2014 Academic Editor: Saulius Butenas Copyright © 2014 M. Barbelanne and W. Y. Tsang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual disability. MCPH is genetically heterogeneous and can exhibit additional clinical features that overlap with related disorders including Seckel syndrome, Meier-Gorlin syndrome, and microcephalic osteodysplastic dwarfism. In this review, we discuss the key proteins mutated in MCPH. To date, MCPH-causing mutations have been identified in twelve different genes, many of which encode proteins that are involved in cell cycle regulation or are present at the centrosome, an organelle crucial for mitotic spindle assembly and cell division. We highlight recent findings on MCPH proteins with regard to their role in cell cycle progression, centrosome function, and early brain development.
    [Show full text]
  • Familial Bone Marrow Monosomy 7 Evidence That the Predisposing Locus Is Not on the Long Arm of Chromosome 7 Kevin M
    Familial Bone Marrow Monosomy 7 Evidence That the Predisposing Locus Is Not on the Long Arm of Chromosome 7 Kevin M. Shannon,* All G. Turhan,*$ Sharon S. Y. Chang,"1 Anne M. Bowcock,' Paul C. J. Rogers,** William L. Carroll,# Morton J. Cowan,* Bertil E. Glader,* Connie J. Eaves, *1111 Allen C. Eaves,t1111 and Yuet Wai Kan1ltl Departments of*Pediatrics and "'Medicine and 1lHoward Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143; Departments of Pathology, **Pediatrics, and 111IMedicine, University ofBritish Columbia, and the §Terry Fox Laboratory, British Columbia Cancer Centre, Vancouver, British Columbia, Canada; Departments of'Genetics and "Pediatrics, Stanford University Medical School, Stanford, California 94303; and t*Department ofPediatrics, Washington University School of Medicine, St. Louis, Missouri 63110 Abstract cinogen exposure (3, 6). The age distribution of these de novo cases shows peaks in the first and fifth decades (6). Overall, Loss of expression of a tumor-suppressing gene is an attractive monosomy 7 or 7q- is identified in - 5% of de novo and in model to explain the cytogenetic and epidemiologic features of 40% of secondary cases of AML (1, 3-5). Although childhood cases of myelodysplasia and acute myelogenous leukemia bone marrow monosomy 7 is an uncommon disorder, it has (AML) associated with bone marrow monosomy 7 or partial been observed in two or more siblings at least seven times deletion of the long arm (7q-). We used probes from within the (7-10, Lange, B. J., personal communication, and our unpub- breakpoint region on 7q- chromosomes (7q22-34) that detect lished data).
    [Show full text]
  • The Cytogenetics of Hematologic Neoplasms 1 5
    The Cytogenetics of Hematologic Neoplasms 1 5 Aurelia Meloni-Ehrig that errors during cell division were the basis for neoplastic Introduction growth was most likely the determining factor that inspired early researchers to take a better look at the genetics of the The knowledge that cancer is a malignant form of uncon- cell itself. Thus, the need to have cell preparations good trolled growth has existed for over a century. Several biologi- enough to be able to understand the mechanism of cell cal, chemical, and physical agents have been implicated in division became of critical importance. cancer causation. However, the mechanisms responsible for About 50 years after Boveri’s chromosome theory, the this uninhibited proliferation, following the initial insult(s), fi rst manuscripts on the chromosome makeup in normal are still object of intense investigation. human cells and in genetic disorders started to appear, fol- The fi rst documented studies of cancer were performed lowed by those describing chromosome changes in neoplas- over a century ago on domestic animals. At that time, the tic cells. A milestone of this investigation occurred in 1960 lack of both theoretical and technological knowledge with the publication of the fi rst article by Nowell and impaired the formulations of conclusions about cancer, other Hungerford on the association of chronic myelogenous leu- than the visible presence of new growth, thus the term neo- kemia with a small size chromosome, known today as the plasm (from the Greek neo = new and plasma = growth). In Philadelphia (Ph) chromosome, to honor the city where it the early 1900s, the fundamental role of chromosomes in was discovered (see also Chap.
    [Show full text]
  • WNT16 Is a New Marker of Senescence
    Table S1. A. Complete list of 177 genes overexpressed in replicative senescence Value Gene Description UniGene RefSeq 2.440 WNT16 wingless-type MMTV integration site family, member 16 (WNT16), transcript variant 2, mRNA. Hs.272375 NM_016087 2.355 MMP10 matrix metallopeptidase 10 (stromelysin 2) (MMP10), mRNA. Hs.2258 NM_002425 2.344 MMP3 matrix metallopeptidase 3 (stromelysin 1, progelatinase) (MMP3), mRNA. Hs.375129 NM_002422 2.300 HIST1H2AC Histone cluster 1, H2ac Hs.484950 2.134 CLDN1 claudin 1 (CLDN1), mRNA. Hs.439060 NM_021101 2.119 TSPAN13 tetraspanin 13 (TSPAN13), mRNA. Hs.364544 NM_014399 2.112 HIST2H2BE histone cluster 2, H2be (HIST2H2BE), mRNA. Hs.2178 NM_003528 2.070 HIST2H2BE histone cluster 2, H2be (HIST2H2BE), mRNA. Hs.2178 NM_003528 2.026 DCBLD2 discoidin, CUB and LCCL domain containing 2 (DCBLD2), mRNA. Hs.203691 NM_080927 2.007 SERPINB2 serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), mRNA. Hs.594481 NM_002575 2.004 HIST2H2BE histone cluster 2, H2be (HIST2H2BE), mRNA. Hs.2178 NM_003528 1.989 OBFC2A Oligonucleotide/oligosaccharide-binding fold containing 2A Hs.591610 1.962 HIST2H2BE histone cluster 2, H2be (HIST2H2BE), mRNA. Hs.2178 NM_003528 1.947 PLCB4 phospholipase C, beta 4 (PLCB4), transcript variant 2, mRNA. Hs.472101 NM_182797 1.934 PLCB4 phospholipase C, beta 4 (PLCB4), transcript variant 1, mRNA. Hs.472101 NM_000933 1.933 KRTAP1-5 keratin associated protein 1-5 (KRTAP1-5), mRNA. Hs.534499 NM_031957 1.894 HIST2H2BE histone cluster 2, H2be (HIST2H2BE), mRNA. Hs.2178 NM_003528 1.884 CYTL1 cytokine-like 1 (CYTL1), mRNA. Hs.13872 NM_018659 tumor necrosis factor receptor superfamily, member 10d, decoy with truncated death domain (TNFRSF10D), 1.848 TNFRSF10D Hs.213467 NM_003840 mRNA.
    [Show full text]
  • Gene Mapping of Familial Autosomal Dominant Dilated Cardiomyopathy to Chromosome 10Q21-23
    Gene mapping of familial autosomal dominant dilated cardiomyopathy to chromosome 10q21-23. K R Bowles, … , R Pignatelli, J A Towbin J Clin Invest. 1996;98(6):1355-1360. https://doi.org/10.1172/JCI118922. Research Article Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disorder, accounting for 60% of all cardiomyopathies. In 20-30% of cases, familial inheritance can be demonstrated; an autosomal dominant transmission is the usual type of inheritance pattern identified. Previously, genetic heterogeneity was demonstrated in familial autosomal dominant dilated cardiomyopathy (FDCM). Gene localization to chromosome 1 (1p1-1q1 and 1q32), chromosome 3 (3p25-3p22), and chromosome 9 (9q13-9q22) has recently been identified. We report one family with 26 members (12 affected) with familial autosomal dominant dilated cardiomyopathy in which linkage to chromosome 10 at the 10q21-q23 locus is identified. Using short tandem repeat polymorphism (STR) markers with heterozygosity > 70%, 169 markers (50% of the genome) were used before linkage was found to markers D10S605 and D10S201 with a pairwise LOD score = 3.91, theta = 0, penetrance = 100% for both markers. Linkage to 1p1-1q1, 1q32, 3p25-3p22, and 9q13-9q22 was excluded. We conclude that a new locus for pure autosomal dominant FDCM exists, and that this gene is localized to a 9 cM region of 10q21-10q23. The search for the disease causing gene and the responsible mutation(s) is ongoing. Find the latest version: https://jci.me/118922/pdf Gene Mapping of Familial Autosomal Dominant Dilated Cardiomyopathy to Chromosome 10q21-23 Karla R. Bowles,* Robert Gajarski,‡ Patrick Porter,‡ Veronica Goytia,‡ Linda Bachinski,ʈ Robert Roberts,ʈ Ricardo Pignatelli,‡ and Jeffrey A.
    [Show full text]