title: MUTYH gene expression and alternative splicing in controls and polyposis patients.
abstract: Mutational loss of the human DNA repair gene MUTYH in the germline predisposes for colorectal polyposis and cancer, a recessively heritable disease called MUTYH-associated polyposis. The MUTYH gene shows heavy alternative splicing, but the transcripts relevant for biological function and cancer prevention have not been determined. This knowledge is required to assess the consequences that germline variants of unknown functional significance may have. We therefore quantified expression and investigated patterns of alternative splicing in control individuals, tissue samples, and carriers of two frequent germline alterations. MUTYH expression differed organ dependently, correlating with proliferative activity. Alternative first exons were used tissue specifically; transcripts for mitochondrial proteins predominated in muscle tissues, while ascending colon and testes showed the highest fractions of transcripts for nuclear proteins. Colon cancer cell lines produced predominant transcripts for nuclear protein. Exon skipping was frequent and governed by splice-site quality. Five transcripts were found to encode the biologically relevant products of the MUTYH gene. Carriers of the disease-causing mutation c.1187G>A (p.Gly396Asp) showed normal transcript composition, but the frequent single-nucleotide polymorphism rs3219468:G>C largely reduced one transcript species of MUTYH. Since this alteration decreases protein production of the gene, an increased cancer risk for compound heterozygous carriers is possible.
authors.affiliation: Biomedical Research Laboratory, Medizinische Klinik 1, Klinik der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt, Germany. plotz@med.uni-frankfurt.de
authors.forename: Guido
authors.initials: G
authors.lastname: Plotz
authors.forename: Markus
authors.initials: M
authors.lastname: Casper
authors.forename: Jochen
authors.initials: J
authors.lastname: Raedle
authors.forename: Inga
authors.initials: I
authors.lastname: Hinrichsen
authors.forename: Verena
authors.initials: V
authors.lastname: Heckel
authors.forename: Angela
authors.initials: A
authors.lastname: Brieger
authors.forename: Jörg
authors.initials: J
authors.lastname: Trojan
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase