title: A germline mutation in SRRM2, a splicing factor gene, is implicated in papillary thyroid carcinoma predisposition.
abstract: Papillary thyroid carcinoma (PTC) displays strong but so far largely uncharacterized heritability. Here we studied genetic predisposition in a family with six affected individuals. We genotyped all available family members and conducted whole exome sequencing of blood DNA from two affected individuals. Haplotype analysis and other genetic criteria narrowed our list of candidates to a germline variant in the serine/arginine repetitive matrix 2 gene (SRRM2). This heterozygous variant, c.1037C > T (Ser346Phe or S346F; rs149019598) cosegregated with PTC in the family. It was not found in 138 other PTC families. It was found in 7/1,170 sporadic PTC cases and in 0/1,404 controls (p = 0.004). The encoded protein SRRM2 (also called SRm300) is part of the RNA splicing machinery. To evaluate the possibility that the S346F missense mutation affects alternative splicing, we compared RNA-Seq data in leukocytes from three mutation carriers and three controls. Significant differences in alternative splicing were identified for 1,642 exons, of which a subset of 7 exons was verified experimentally. The results confirmed a higher ratio of inclusion of exons in mutation carriers. These data suggest that the S346F mutation in SRRM2 predisposes to PTC by affecting alternative splicing of unidentified downstream target genes.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Jerneja
authors.initials: J
authors.lastname: Tomsic
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Huiling
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.affiliation: Banting and Best Department of Medical Research, University of Toronto, Toronto, Canada.
authors.forename: Qun
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Blake
authors.initials: B
authors.lastname: Bertani
authors.affiliation: Department of Internal Medicine, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nagy
authors.affiliation: 1] Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America [2] Department of Internal Medicine, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America [3] Department of Biomedical Informatics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, the Ohio State University, Columbus, Ohio, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Symer
authors.affiliation: 1] Banting and Best Department of Medical Research, University of Toronto, Toronto, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D002291:Carcinoma, Papillary / Q000235:genetics*; D016022:Case-Control Studies; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D016601:RNA-Binding Proteins; C414618:SRRM2 protein, human