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American Journal of Human GeneticsVolume 101, Issue 1, 6 July 2017, Pages 87-103

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia(Article)(Open Access)

  • Seixas, A.I.,
  • Loureiro, J.R.,
  • Costa, C.,
  • Ordóñez-Ugalde, A.,
  • Marcelino, H.,
  • Oliveira, C.L.,
  • Loureiro, J.L.,
  • Dhingra, A.,
  • Brandão, E.,
  • Cruz, V.T.,
  • Timóteo, A.,
  • Quintáns, B.,
  • Rouleau, G.A.,
  • Rizzu, P.,
  • Carracedo, Á.,
  • Bessa, J.,
  • Heutink, P.,
  • Sequeiros, J.,
  • Sobrido, M.J.,
  • Coutinho, P.,
  • Silveira, I.
  • View Correspondence (jump link)
  • aUnIGENe, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal
  • bInstitute for Molecular and Cell Biology, Universidade do Porto, Porto, 4200-135, Portugal
  • cGenetics of Cognitive Dysfunction Laboratory, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal
  • dInstituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, 4050-313, Portugal
  • eDepartment of Neurology, Hospital Prof. Doutor Fernando Fonseca EPE, Amadora, 2720-276, Portugal
  • fInstituto de Investigación Sanitaria and Fundación Pública Galega de Medicina Xenómica, Centro para Investigación Biomédica en Red de Enfermedades Raras, Santiago de Compostela, 15706, Spain
  • gVertebrate Development and Regeneration Laboratory, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal
  • hDepartment of Neurology, Hospital São Sebastião, Feira, 4520-211, Portugal
  • iGerman Center for Neurodegenerative Diseases, Tübingen, 72076, Germany
  • jMontreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 2B4, Canada
  • kGlial Cell Biology Laboratory, Instituto de Investigação e Inovação em Saúde, Institute for Molecular and Cell Biology, Universidade do Porto, Porto, 4200-135, Portugal

Abstract

Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC)n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT)7–400] and [(ATTTT)60–79(ATTTC)31–75(ATTTT)58–90], respectively. (ATTTC)n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC)n is located in 5′ UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC)58 insertion, but not (ATTTT)n, leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC)58 insertion, but not (AUUUU)n, showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37. © 2017 American Society of Human Genetics

Author keywords

DAB1 reelin adaptor proteinlarge Alu pentanucleotide repeatneurodegenerationneurodegenerative diseaseneurodevelopmental generepeat expansionrepeat instabilityRNA-mediated toxicitySCA37unstable repeat insertion

Indexed keywords

EMTREE drug terms:genomic DNAmessenger RNAnuclear RNAspacer DNAuntranslated RNADAB1 protein, humanmessenger RNAmicrosatellite DNAnerve proteinRNAsignal transducing adaptor proteinspacer DNA
EMTREE medical terms:adultalleleanimal experimentArticlebrain developmentchromosomal mappingchromosome 1pDAB1 geneembryofemalefetusfetus brainfluorescence in situ hybridizationgenegene expressiongene insertion sequencegene mappinggenome-wide association studygenotypehaplotypeHEK293T cell linehumanhuman celllinkage analysismalenonhumanpriority journalSCA37 genesingle nucleotide polymorphismSouthern blottingspinocerebellar degenerationzebra fishadolescentcerebellumchromosomal mappingchromosome 1chromosome segregationdna mutational analysisembryo developmentgene expression regulationgenetic predispositiongeneticsHEK293 cell lineintronmetabolismmiddle agednucleotide sequenceonset agepedigreespinocerebellar degenerationyoung adult
MeSH:Adaptor Proteins, Signal TransducingAdolescentAdultAge of OnsetAllelesBase SequenceCerebellumChromosome SegregationChromosomes, Human, Pair 1DNA Mutational AnalysisDNA, IntergenicEmbryonic DevelopmentFemaleGenetic Predisposition to DiseaseHaplotypesHEK293 CellsHumansIntronsMaleMicrosatellite RepeatsMiddle AgedMutagenesis, InsertionalNerve Tissue ProteinsPedigreePhysical Chromosome MappingRNARNA, MessengerSpinocerebellar AtaxiasYoung Adult

Chemicals and CAS Registry Numbers:

RNA, 63231-63-0;

Adaptor Proteins, Signal Transducing; DAB1 protein, human; DNA, Intergenic; Nerve Tissue Proteins; RNA; RNA, Messenger

Funding details

Funding sponsor Funding number Acronym
SFRH/BD/30702/2006,PEst-C/SAU/LA0002/2013
Fundação Portugal Telecom
European Molecular Biology Organization
See opportunities		ASTF494-2015,Norte-01-0145-FEDER-000008
Instituto de Salud Carlos IIIPI12/00742
Fundação para a Ciência e a Tecnologia
See opportunities
POCI-01-0145-FEDER-007274,PTDC/SAU-GMG/098305/2008
POCI,2020
European Regional Development Fund
Institute of Molecular and Cell Biology
NORTE

  • 1

    We thank the families who participated in this study. We are grateful to Gon?alo Abecasis, Miguel Costa, Tito Vieira, and Andr? Torres for help with MERLIN analysis; Beatriz Sobrino, Jorge Amigo, and Pilar Cacheiro for next-generation sequencing analysis, performed at the Santiago de Compostela node of the Spanish National Genotyping Center; Nuno Santar?m and Anabela Cordeiro-da-Silva for assistance with cloning; Ant?nio Amorim, Laura Vilarinho, and Paula Jorge for samples from the Portuguese population; and Paula Magalh?es from the Institute for Molecular and Cell Biology Cell Culture and Genotyping Core for DNA extraction. This work was financed by Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020 Operational Program for Competitiveness and Internationalization (POCI) of Portugal 2020 and by Portuguese funds through the Funda??o para a Ci?ncia e a Tecnologia (FCT) and Minist?rio da Ci?ncia, Tecnologia, e Inova??o in the framework of the project ?Institute for Research and Innovation in Health Sciences? (POCI-01-0145-FEDER-007274); and by FCT?grant PTDC/SAU-GMG/098305/2008 to I.S. A.I.S. was the recipient of an FCT scholarship (SFRH/BD/30702/2006). J.R.L. was supported by scholarships from PEst-C/SAU/LA0002/2013 and the European Molecular Biology Organization (ASTF494-2015). C.L.O. was supported by a scholarship from PEst-C/SAU/LA0002/2013. This work was also financed by the Porto Neurosciences and Neurologic Disease Research Initiative at the Instituto de Investiga??o e Inova??o em Sa?de (Norte-01-0145-FEDER-000008), supported by Norte Portugal Regional Operational Programme (NORTE 2020) under the PORTUGAL 2020 Partnership Agreement through FEDER, and by the Fondo de Investigaci?n Sanitaria of the Instituto de Salud Carlos III (grant PI12/00742).

  • ISSN: 00029297
  • CODEN: AJHGA
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1016/j.ajhg.2017.06.007
  • PubMed ID: 28686858
  • Document Type: Article
  • Publisher: Cell Press

  Silveira, I.; Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal;
© Copyright 2017 Elsevier B.V., All rights reserved.

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