Author | White, Janson | |
Author | Araújo, Juliana Forte Mazzeu de | |
Author | Hoischen, Alexander | |
Author | Jhangiani, Shalini N. | |
Author | Gambin, Tomasz | |
Author | Alcino, Michele Calijorne | |
Author | Penney, Samantha | |
Author | Saraiva, Jorge M. | |
Author | Hove, Hanne | |
Author | Skovby, Flemming | |
Author | Kayserili, Hu¨lya | |
Author | Estrella, Elicia | |
Author | Vulto-van Silfhout, Anneke T. | |
Author | Steehouwer, Marloes | |
Author | Muzny, Donna M. | |
Author | Sutton, V. Reid | |
Author | Gibbs, Richard A. | |
Author | Lupski, James R. | |
Author | van Bon, Bregje W.M. | |
Access date | 2016-01-19T17:57:35Z | |
Available date | 2016-01-19T17:57:35Z | |
Document date | 2015 | |
Citation | WHITE, Janson et al. DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome. Am J Hum Genet., vol. 96, n. 4, p. 612-22. 2015 | pt_BR |
ISSN | 0002-9297 | |
URI | https://www.arca.fiocruz.br/handle/icict/12561 | |
Language | eng | pt_BR |
Publisher | Elsevier Inc. | pt_BR |
Rights | open access | pt_BR |
Title | DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome | pt_BR |
Type | Article | pt_BR |
DOI | 10.1016/j.ajhg.2015.02.015 | |
Abstract | Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS. | pt_BR |
Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA | pt_BR |
Affilliation | Universidade Catolica de Brasılia. Programa de Pos-graduaçao em Ciencias Genomicas e Biotecnologia. Brasılia, DF, Brasil/Robinow Syndrome Foundation. Anoka, MN, USA | pt_BR |
Affilliation | Radboud University Medical Center. Radboud Institute for Molecular Life Sciences. Department of Human Genetics. Nijmegen, the Netherlands | pt_BR |
Affilliation | Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA | pt_BR |
Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Warsaw University of Technology. Institute of Computer Science. Warsaw, Poland | pt_BR |
Affilliation | Fundaçao Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG, Brasil | pt_BR |
Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA | pt_BR |
Affilliation | Centro Hospitalar e Universitario de Coimbra. Hospital Pediatrico. Medical Genetics Unit. Coimbra, Portugal/University of Coimbra. University Clinic of Pediatrics. Faculty of Medicine. Coimbra, Portugal | pt_BR |
Affilliation | University of Copenhagen. Rigshospitalet. Department of Clinical Genetics. Copenhagen, Denmark | pt_BR |
Affilliation | University of Copenhagen. Rigshospitalet. Department of Clinical Genetics. Copenhagen, Denmark | pt_BR |
Affilliation | Istanbul University. Istanbul Medical Faculty. Medical Genetics Department. Istanbul, Turkey/Koc University, Rumelifeneri Yolu. School of Medicine. Medical Genetics Department. Sariyer Istanbul,Turkey | pt_BR |
Affilliation | Boston Children’s Hospital and Harvard Medical School. Department of Genetics & Genomics. Boston, MA, USA | pt_BR |
Affilliation | Radboud University Medical Center. Radboud Institute for Molecular Life Sciences. Department of Human Genetics. Nijmegen, the Netherlands | pt_BR |
Affilliation | Radboud University Medical Center. Radboud Institute for Molecular Life Sciences. Department of Human Genetics. Nijmegen, the Netherlands | pt_BR |
Affilliation | Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA | pt_BR |
Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/ Texas Children’s Hospital. Houston, TX, USA | pt_BR |
Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA | pt_BR |
Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA/Texas Children’s Hospital. Houston, TX, USA/Baylor College of Medicine. Department of Pediatrics. Houston, TX, USA Han G. Brunner | pt_BR |
Affilliation | Radboud University Medical Center. Radboud Institute for Molecular Life Sciences. Department of Human Genetics. Nijmegen, the Netherlands | pt_BR |
Subject | Adaptor Proteins | pt_BR |
Subject | Signal Transducing/genetics | pt_BR |
Subject | Craniofacial Abnormalities/genetics | pt_BR |
Subject | Frameshift Mutation/genetics | pt_BR |
Subject | Limb Deformities, Congenital/genetics | pt_BR |
Subject | Molecular Sequence Data | pt_BR |
Subject | Urogenital Abnormalities/genetics | pt_BR |