000139358 001__ 139358
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000139358 0247_ $$2doi$$a10.1016/j.ajhg.2017.06.007
000139358 0247_ $$2pmid$$apmid:28686858
000139358 0247_ $$2pmc$$apmc:PMC5501871
000139358 0247_ $$2ISSN$$a0002-9297
000139358 0247_ $$2ISSN$$a1537-6605
000139358 0247_ $$2altmetric$$aaltmetric:21560185
000139358 037__ $$aDZNE-2020-05680
000139358 041__ $$aEnglish
000139358 082__ $$a570
000139358 1001_ $$aSeixas, Ana I$$b0
000139358 245__ $$aA Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia.
000139358 260__ $$aNew York, NY$$bElsevier$$c2017
000139358 264_1 $$2Crossref$$3print$$bElsevier BV$$c2017-07-01
000139358 3367_ $$2DRIVER$$aarticle
000139358 3367_ $$2DataCite$$aOutput Types/Journal article
000139358 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1710344181_30566
000139358 3367_ $$2BibTeX$$aARTICLE
000139358 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000139358 3367_ $$00$$2EndNote$$aJournal Article
000139358 520__ $$aAdvances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC)n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT)7-400] and [(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90], respectively. (ATTTC)n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC)n is located in 5' UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC)58 insertion, but not (ATTTT)n, leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC)58 insertion, but not (AUUUU)n, showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37.
000139358 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000139358 536__ $$0G:(DE-HGF)POF3-345$$a345 - Population Studies and Genetics (POF3-345)$$cPOF3-345$$fPOF III$$x1
000139358 542__ $$2Crossref$$i2017-07-01$$uhttps://www.elsevier.com/tdm/userlicense/1.0/
000139358 542__ $$2Crossref$$i2018-01-06$$uhttps://www.elsevier.com/open-access/userlicense/1.0/
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000139358 650_7 $$2NLM Chemicals$$aAdaptor Proteins, Signal Transducing
000139358 650_7 $$2NLM Chemicals$$aDAB1 protein, human
000139358 650_7 $$2NLM Chemicals$$aDNA, Intergenic
000139358 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000139358 650_7 $$2NLM Chemicals$$aRNA, Messenger
000139358 650_7 $$063231-63-0$$2NLM Chemicals$$aRNA
000139358 650_2 $$2MeSH$$aReelin Protein
000139358 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: genetics
000139358 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: metabolism
000139358 650_2 $$2MeSH$$aAdolescent
000139358 650_2 $$2MeSH$$aAdult
000139358 650_2 $$2MeSH$$aAge of Onset
000139358 650_2 $$2MeSH$$aAlleles
000139358 650_2 $$2MeSH$$aBase Sequence
000139358 650_2 $$2MeSH$$aCerebellum: metabolism
000139358 650_2 $$2MeSH$$aChromosome Segregation: genetics
000139358 650_2 $$2MeSH$$aChromosomes, Human, Pair 1: genetics
000139358 650_2 $$2MeSH$$aDNA Mutational Analysis
000139358 650_2 $$2MeSH$$aDNA, Intergenic: genetics
000139358 650_2 $$2MeSH$$aEmbryonic Development: genetics
000139358 650_2 $$2MeSH$$aFemale
000139358 650_2 $$2MeSH$$aGenetic Predisposition to Disease
000139358 650_2 $$2MeSH$$aHEK293 Cells
000139358 650_2 $$2MeSH$$aHaplotypes: genetics
000139358 650_2 $$2MeSH$$aHumans
000139358 650_2 $$2MeSH$$aIntrons: genetics
000139358 650_2 $$2MeSH$$aMale
000139358 650_2 $$2MeSH$$aMicrosatellite Repeats: genetics
000139358 650_2 $$2MeSH$$aMiddle Aged
000139358 650_2 $$2MeSH$$aMutagenesis, Insertional: genetics
000139358 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000139358 650_2 $$2MeSH$$aNerve Tissue Proteins: metabolism
000139358 650_2 $$2MeSH$$aPedigree
000139358 650_2 $$2MeSH$$aPhysical Chromosome Mapping
000139358 650_2 $$2MeSH$$aRNA: genetics
000139358 650_2 $$2MeSH$$aRNA, Messenger: genetics
000139358 650_2 $$2MeSH$$aRNA, Messenger: metabolism
000139358 650_2 $$2MeSH$$aSpinocerebellar Ataxias: genetics
000139358 650_2 $$2MeSH$$aYoung Adult
000139358 7001_ $$0P:(DE-HGF)0$$aLoureiro, Joana R$$b1
000139358 7001_ $$aCosta, Cristina$$b2
000139358 7001_ $$aOrdóñez-Ugalde, Andrés$$b3
000139358 7001_ $$aMarcelino, Hugo$$b4
000139358 7001_ $$aOliveira, Cláudia L$$b5
000139358 7001_ $$aLoureiro, José L$$b6
000139358 7001_ $$0P:(DE-HGF)0$$aDhingra, Ashutosh$$b7
000139358 7001_ $$aBrandão, Eva$$b8
000139358 7001_ $$aCruz, Vitor T$$b9
000139358 7001_ $$aTimóteo, Angela$$b10
000139358 7001_ $$aQuintáns, Beatriz$$b11
000139358 7001_ $$aRouleau, Guy A$$b12
000139358 7001_ $$0P:(DE-2719)2810718$$aRizzu, Patrizia$$b13$$udzne
000139358 7001_ $$aCarracedo, Ángel$$b14
000139358 7001_ $$aBessa, José$$b15
000139358 7001_ $$0P:(DE-2719)2810728$$aHeutink, Peter$$b16$$udzne
000139358 7001_ $$aSequeiros, Jorge$$b17
000139358 7001_ $$aSobrido, Maria J$$b18
000139358 7001_ $$aCoutinho, Paula$$b19
000139358 7001_ $$0P:(DE-HGF)0$$aSilveira, Isabel$$b20$$eCorresponding author
000139358 77318 $$2Crossref$$3journal-article$$a10.1016/j.ajhg.2017.06.007$$b : Elsevier BV, 2017-07-01$$n1$$p87-103$$tThe American Journal of Human Genetics$$v101$$x0002-9297$$y2017
000139358 773__ $$0PERI:(DE-600)1473813-2$$a10.1016/j.ajhg.2017.06.007$$gVol. 101, no. 1, p. 87 - 103$$n1$$p87-103$$q101:1<87 - 103$$tThe American journal of human genetics$$v101$$x0002-9297$$y2017
000139358 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501871
000139358 8564_ $$uhttps://pub.dzne.de/record/139358/files/DZNE-2020-05680_Restricted.pdf
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