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@ARTICLE{Seixas:139358,
      author       = {Seixas, Ana I and Loureiro, Joana R and Costa, Cristina and
                      Ordóñez-Ugalde, Andrés and Marcelino, Hugo and Oliveira,
                      Cláudia L and Loureiro, José L and Dhingra, Ashutosh and
                      Brandão, Eva and Cruz, Vitor T and Timóteo, Angela and
                      Quintáns, Beatriz and Rouleau, Guy A and Rizzu, Patrizia
                      and Carracedo, Ángel and Bessa, José and Heutink, Peter
                      and Sequeiros, Jorge and Sobrido, Maria J and Coutinho,
                      Paula and Silveira, Isabel},
      title        = {{A} {P}entanucleotide {ATTTC} {R}epeat {I}nsertion in the
                      {N}on-coding {R}egion of {DAB}1, {M}apping to {SCA}37,
                      {C}auses {S}pinocerebellar {A}taxia.},
      journal      = {The American journal of human genetics},
      volume       = {101},
      number       = {1},
      issn         = {0002-9297},
      address      = {New York, NY},
      publisher    = {Elsevier},
      reportid     = {DZNE-2020-05680},
      pages        = {87-103},
      year         = {2017},
      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.},
      keywords     = {Reelin Protein / Adaptor Proteins, Signal Transducing:
                      genetics / Adaptor Proteins, Signal Transducing: metabolism
                      / Adolescent / Adult / Age of Onset / Alleles / Base
                      Sequence / Cerebellum: metabolism / Chromosome Segregation:
                      genetics / Chromosomes, Human, Pair 1: genetics / DNA
                      Mutational Analysis / DNA, Intergenic: genetics / Embryonic
                      Development: genetics / Female / Genetic Predisposition to
                      Disease / HEK293 Cells / Haplotypes: genetics / Humans /
                      Introns: genetics / Male / Microsatellite Repeats: genetics
                      / Middle Aged / Mutagenesis, Insertional: genetics / Nerve
                      Tissue Proteins: genetics / Nerve Tissue Proteins:
                      metabolism / Pedigree / Physical Chromosome Mapping / RNA:
                      genetics / RNA, Messenger: genetics / RNA, Messenger:
                      metabolism / Spinocerebellar Ataxias: genetics / Young Adult
                      / Adaptor Proteins, Signal Transducing (NLM Chemicals) /
                      DAB1 protein, human (NLM Chemicals) / DNA, Intergenic (NLM
                      Chemicals) / Nerve Tissue Proteins (NLM Chemicals) / RNA,
                      Messenger (NLM Chemicals) / RNA (NLM Chemicals)},
      cin          = {AG Rizzu / AG Heutink},
      ddc          = {570},
      cid          = {I:(DE-2719)1210009 / I:(DE-2719)1210002},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 345
                      - Population Studies and Genetics (POF3-345)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-345},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28686858},
      pmc          = {pmc:PMC5501871},
      doi          = {10.1016/j.ajhg.2017.06.007},
      url          = {https://pub.dzne.de/record/139358},
}