2. Academic Validation
  3. A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia

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

  • Am J Hum Genet. 2017 Jul 6;101(1):87-103. doi: 10.1016/j.ajhg.2017.06.007.
Ana I Seixas 1,  Joana R Loureiro 2,  Cristina Costa 3,  Andrés Ordóñez-Ugalde 4,  Hugo Marcelino 5,  Cláudia L Oliveira 6,  José L Loureiro 7,  Ashutosh Dhingra 8,  Eva Brandão 9,  Vitor T Cruz 9,  Angela Timóteo 3,  Beatriz Quintáns 10,  Guy A Rouleau 11,  Patrizia Rizzu 8,  Ángel Carracedo 10,  José Bessa 5,  Peter Heutink 8,  Jorge Sequeiros 12,  Maria J Sobrido 10,  Paula Coutinho 1,  Isabel Silveira 13
Affiliations

Affiliations

  • 1 UnIGENe, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; Institute for Molecular and Cell Biology, Universidade do Porto, 4200-135 Porto, Portugal.
  • 2 Institute for Molecular and Cell Biology, Universidade do Porto, 4200-135 Porto, Portugal; Genetics of Cognitive Dysfunction Laboratory, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal.
  • 3 Department of Neurology, Hospital Prof. Doutor Fernando Fonseca EPE, 2720-276 Amadora, Portugal.
  • 4 Institute for Molecular and Cell Biology, Universidade do Porto, 4200-135 Porto, Portugal; Genetics of Cognitive Dysfunction Laboratory, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; Instituto de Investigación Sanitaria and Fundación Pública Galega de Medicina Xenómica, Centro para Investigación Biomédica en Red de Enfermedades Raras, 15706 Santiago de Compostela, Spain.
  • 5 Institute for Molecular and Cell Biology, Universidade do Porto, 4200-135 Porto, Portugal; Vertebrate Development and Regeneration Laboratory, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
  • 6 Institute for Molecular and Cell Biology, Universidade do Porto, 4200-135 Porto, Portugal; Genetics of Cognitive Dysfunction Laboratory, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
  • 7 UnIGENe, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; Institute for Molecular and Cell Biology, Universidade do Porto, 4200-135 Porto, Portugal; Department of Neurology, Hospital São Sebastião, 4520-211 Feira, Portugal.
  • 8 German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany.
  • 9 Department of Neurology, Hospital São Sebastião, 4520-211 Feira, Portugal.
  • 10 Instituto de Investigación Sanitaria and Fundación Pública Galega de Medicina Xenómica, Centro para Investigación Biomédica en Red de Enfermedades Raras, 15706 Santiago de Compostela, Spain.
  • 11 Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 2B4, Canada.
  • 12 UnIGENe, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; Institute for Molecular and Cell Biology, Universidade do Porto, 4200-135 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal.
  • 13 Institute for Molecular and Cell Biology, Universidade do Porto, 4200-135 Porto, Portugal; Genetics of Cognitive Dysfunction Laboratory, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal. Electronic address: [email protected].
PMID: 28686858 DOI: 10.1016/j.ajhg.2017.06.007
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

DAB1 reelin adaptor protein; RNA-mediated toxicity; SCA37; large Alu pentanucleotide repeat; neurodegeneration; neurodegenerative disease; neurodevelopmental gene; repeat expansion; repeat instability; unstable repeat insertion.

Figures