title: Familial retinoblastoma due to intronic LINE-1 insertion causes aberrant and noncanonical mRNA splicing of the RB1 gene.
abstract: Retinoblastoma (RB, MIM 180200) is the paradigm of hereditary cancer. Individuals harboring a constitutional mutation in one allele of the RB1 gene have a high predisposition to develop RB. Here, we present the first case of familial RB caused by a de novo insertion of a full-length long interspersed element-1 (LINE-1) into intron 14 of the RB1 gene that caused a highly heterogeneous splicing pattern of RB1 mRNA. LINE-1 insertion was inferred by mRNA studies and full-length sequenced by massive parallel sequencing. Some of the aberrant mRNAs were produced by noncanonical acceptor splice sites, a new finding that up to date has not been described to occur upon LINE-1 retrotransposition. Our results clearly show that RNA-based strategies have the potential to detect disease-causing transposon insertions. It also confirms that the incorporation of new genetic approaches, such as massive parallel sequencing, contributes to characterize at the sequence level these unique and exceptional genetic alterations.
authors.affiliation: Unidad de Tumores Sólidos Infantiles, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodríguez-Martín
authors.affiliation: Unidad de Tumores Sólidos Infantiles, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Florencia
authors.initials: F
authors.lastname: Cidre
authors.affiliation: Unidad de Gestión Clínica Intercentros de Oncología Pediátricas, Hospitales Universitarios Virgen Macarena y Virgen del Rocío, National Reference Unit for Retinoblastoma, Sevilla, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández-Teijeiro
authors.affiliation: Unidad de Tumores Sólidos Infantiles, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Gómez-Mariano
authors.affiliation: Unidad de Tumores Sólidos Infantiles, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: de la Vega
authors.affiliation: Unidad de Tumores Sólidos Infantiles, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ramos
authors.affiliation: Unidad de Genómica, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Zaballos
authors.affiliation: Unidad de Tumores Sólidos Infantiles, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U758), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Monzón
authors.affiliation: Unidad de Tumores Sólidos Infantiles, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Alonso
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D019295:Computational Biology / Q000379:methods; D005091:Exons; D056426:Genetic Loci; D006801:Humans; D007223:Infant; D007438:Introns; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D016254:Mutagenesis, Insertional; D012175:Retinoblastoma / Q000175:diagnosis / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D016160:Retinoblastoma Protein