Home > Publications Database > A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia. > print

001     139358
005     20240321220614.0
024 7 _ |a 10.1016/j.ajhg.2017.06.007
|2 doi
024 7 _ |a pmid:28686858
|2 pmid
024 7 _ |a pmc:PMC5501871
|2 pmc
024 7 _ |a 0002-9297
|2 ISSN
024 7 _ |a 1537-6605
|2 ISSN
024 7 _ |a altmetric:21560185
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037 _ _ |a DZNE-2020-05680
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Seixas, Ana I
|b 0
245 _ _ |a A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia.
260 _ _ |a New York, NY
|c 2017
|b Elsevier
264 _ 1 |3 print
|2 Crossref
|b Elsevier BV
|c 2017-07-01
336 7 _ |a article
|2 DRIVER
336 7 _ |a Output Types/Journal article
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336 7 _ |a Journal Article
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|m journal
|0 PUB:(DE-HGF)16
|s 1710344181_30566
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336 7 _ |a ARTICLE
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336 7 _ |a JOURNAL_ARTICLE
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336 7 _ |a Journal Article
|0 0
|2 EndNote
520 _ _ |a 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.
536 _ _ |a 342 - Disease Mechanisms and Model Systems (POF3-342)
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536 _ _ |a 345 - Population Studies and Genetics (POF3-345)
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542 _ _ |i 2017-07-01
|2 Crossref
|u https://www.elsevier.com/tdm/userlicense/1.0/
542 _ _ |i 2018-01-06
|2 Crossref
|u https://www.elsevier.com/open-access/userlicense/1.0/
588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 7 |a Adaptor Proteins, Signal Transducing
|2 NLM Chemicals
650 _ 7 |a DAB1 protein, human
|2 NLM Chemicals
650 _ 7 |a DNA, Intergenic
|2 NLM Chemicals
650 _ 7 |a Nerve Tissue Proteins
|2 NLM Chemicals
650 _ 7 |a RNA, Messenger
|2 NLM Chemicals
650 _ 7 |a RNA
|0 63231-63-0
|2 NLM Chemicals
650 _ 2 |a Reelin Protein
|2 MeSH
650 _ 2 |a Adaptor Proteins, Signal Transducing: genetics
|2 MeSH
650 _ 2 |a Adaptor Proteins, Signal Transducing: metabolism
|2 MeSH
650 _ 2 |a Adolescent
|2 MeSH
650 _ 2 |a Adult
|2 MeSH
650 _ 2 |a Age of Onset
|2 MeSH
650 _ 2 |a Alleles
|2 MeSH
650 _ 2 |a Base Sequence
|2 MeSH
650 _ 2 |a Cerebellum: metabolism
|2 MeSH
650 _ 2 |a Chromosome Segregation: genetics
|2 MeSH
650 _ 2 |a Chromosomes, Human, Pair 1: genetics
|2 MeSH
650 _ 2 |a DNA Mutational Analysis
|2 MeSH
650 _ 2 |a DNA, Intergenic: genetics
|2 MeSH
650 _ 2 |a Embryonic Development: genetics
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Genetic Predisposition to Disease
|2 MeSH
650 _ 2 |a HEK293 Cells
|2 MeSH
650 _ 2 |a Haplotypes: genetics
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Introns: genetics
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Microsatellite Repeats: genetics
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a Mutagenesis, Insertional: genetics
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: genetics
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: metabolism
|2 MeSH
650 _ 2 |a Pedigree
|2 MeSH
650 _ 2 |a Physical Chromosome Mapping
|2 MeSH
650 _ 2 |a RNA: genetics
|2 MeSH
650 _ 2 |a RNA, Messenger: genetics
|2 MeSH
650 _ 2 |a RNA, Messenger: metabolism
|2 MeSH
650 _ 2 |a Spinocerebellar Ataxias: genetics
|2 MeSH
650 _ 2 |a Young Adult
|2 MeSH
700 1 _ |a Loureiro, Joana R
|0 P:(DE-HGF)0
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700 1 _ |a Costa, Cristina
|b 2
700 1 _ |a Ordóñez-Ugalde, Andrés
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700 1 _ |a Marcelino, Hugo
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700 1 _ |a Oliveira, Cláudia L
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700 1 _ |a Loureiro, José L
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700 1 _ |a Dhingra, Ashutosh
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700 1 _ |a Brandão, Eva
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700 1 _ |a Cruz, Vitor T
|b 9
700 1 _ |a Timóteo, Angela
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700 1 _ |a Quintáns, Beatriz
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700 1 _ |a Rouleau, Guy A
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700 1 _ |a Rizzu, Patrizia
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700 1 _ |a Carracedo, Ángel
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700 1 _ |a Bessa, José
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700 1 _ |a Heutink, Peter
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700 1 _ |a Sequeiros, Jorge
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700 1 _ |a Sobrido, Maria J
|b 18
700 1 _ |a Coutinho, Paula
|b 19
700 1 _ |a Silveira, Isabel
|0 P:(DE-HGF)0
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|e Corresponding author
773 1 8 |a 10.1016/j.ajhg.2017.06.007
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|t The American Journal of Human Genetics
|v 101
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773 _ _ |a 10.1016/j.ajhg.2017.06.007
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856 7 _ |2 Pubmed Central
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