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Cis D4Z4 repeat duplications associated with facioscapulohumeral muscular dystrophy type 2.
Lemmers, Richard J L F; van der Vliet, Patrick J; Vreijling, Jeroen P; Henderson, Don; van der Stoep, Nienke; Voermans, Nicol; van Engelen, Baziel; Baas, Frank; Sacconi, Sabrina; Tawil, Rabi; van der Maarel, Silvère M.
Afiliación
  • Lemmers RJLF; Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
  • van der Vliet PJ; Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
  • Vreijling JP; Laboratory for Diagnostic Genome Analysis, Leiden University Medical Center, Leiden, RC, Netherlands.
  • Henderson D; Neuromuscular Disease Unit, Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
  • van der Stoep N; Laboratory for Diagnostic Genome Analysis, Leiden University Medical Center, Leiden, RC, Netherlands.
  • Voermans N; Neuromuscular Centre Nijmegen, Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, HB, Netherlands.
  • van Engelen B; Neuromuscular Centre Nijmegen, Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, HB, Netherlands.
  • Baas F; Laboratory for Diagnostic Genome Analysis, Leiden University Medical Center, Leiden, RC, Netherlands.
  • Sacconi S; Centre de Référence des Maladies Neuromusculaires and CNRS UMR6543, Nice University Hospital, Nice, France.
  • Tawil R; Neuromuscular Disease Unit, Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
  • van der Maarel SM; Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
Hum Mol Genet ; 27(20): 3488-3497, 2018 10 15.
Article en En | MEDLINE | ID: mdl-30281091
Facioscapulohumeral muscular dystrophy, known in genetic forms FSHD1 and FSHD2, is associated with D4Z4 repeat array chromatin relaxation and somatic derepression of DUX4 located in D4Z4. A complete copy of DUX4 is present on 4qA chromosomes, but not on the D4Z4-like repeats of chromosomes 4qB or 10. Normally, the D4Z4 repeat varies between 8 and 100 units, while in FSHD1 it is only 1-10 units. In the rare genetic form FSHD2, a combination of a 4qA allele with a D4Z4 repeat size of 8-20 units and heterozygous pathogenic variants in the chromatin modifier SMCHD1 causes DUX4 derepression and disease. In this study, we identified 11/79 (14%) FSHD2 patients with unusually large 4qA alleles of 21-70 D4Z4 units. By a combination of Southern blotting and molecular combing, we show that 8/11 (73%) of these unusually large 4qA alleles represent duplication alleles in which the long D4Z4 repeat arrays are followed by a small FSHD-sized D4Z4 repeat array duplication. We also show that these duplication alleles are associated with DUX4 expression. This duplication allele frequency is significantly higher than in controls (2.9%), FSHD1 patients (1.4%) and in FSHD2 patients with typical 4qA alleles of 8-20 D4Z4 units (1.5%). Segregation analysis shows that, similar to typical 8-20 units FSHD2 alleles, duplication alleles only cause FSHD in combination with a pathogenic variant in SMCHD1. We conclude that cis duplications of D4Z4 repeats explain DUX4 expression and disease presentation in FSHD2 families with unusual long D4Z4 repeats on 4qA chromosomes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Cromosómicas no Histona / Secuencias Repetitivas de Ácidos Nucleicos / Proteínas de Homeodominio / Distrofia Muscular Facioescapulohumeral / Mutación Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Female / Humans / Male Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2018 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Cromosómicas no Histona / Secuencias Repetitivas de Ácidos Nucleicos / Proteínas de Homeodominio / Distrofia Muscular Facioescapulohumeral / Mutación Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Female / Humans / Male Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2018 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido