title: MUTYH c.933+3A>C, associated with a severely impaired gene expression, is the first Italian founder mutation in MUTYH-Associated Polyposis.
abstract: MUTYH variants are differently distributed in geographical areas of the world. In MUTYH-associated polyposis (MAP) patients from North-Eastern Italy, c.933+3A>C (IVS10+3A>C), a transversion causing an aberrant splicing process, accounts for nearly 1/5 of all mutations. The aim of this study was to verify whether its high frequency in North-Eastern Italy is due to a founder effect and to clarify its impact on MUTYH transcripts and protein. Haplotype analysis and age estimate performed on members of eleven Italian MAP families and cancer-free controls provided evidence that c.933+3A>C is a founder mutation originated about 83 generations ago. In addition, the Italian haplotype associated with the c.933+3A>C was also found in German families segregating the same mutation, indicating it had a common origin in Western Europe. Altogether c.933+3A>C and the two common Caucasian mutations p.Tyr179Cys and p.Gly396Asp represent about 60% of MUTYH alterations in MAP patients from North-Eastern Italy, suggesting the opportunity to perform targeted molecular screening for these variants in the diagnostic setting. Expression analyses performed on lymphoblastoid cell lines supported the notion that MUTYH c.933+3A>C alters splicing causing the synthesis of a non functional protein. However, some primary transcripts escape aberrant splicing, producing traces of full-length transcript and wild-type protein in a homozygote; this is in agreement with clinical findings that suggest a relatively mild phenotypic effect for this mutation. Overall, these data, that demonstrate a founder effect and further elucidate the splicing alterations caused by the MUTYH c.933+3A>C mutation, have important implications for genetic counseling and molecular diagnosis of MAP.
authors.affiliation: Oncologia Sperimentale 1, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pin
authors.forename: Chiara
authors.initials: C
authors.lastname: Pastrello
authors.forename: Rossella
authors.initials: R
authors.lastname: Tricarico
authors.forename: Laura
authors.initials: L
authors.lastname: Papi
authors.forename: Michele
authors.initials: M
authors.lastname: Quaia
authors.forename: Mara
authors.initials: M
authors.lastname: Fornasarig
authors.forename: Ileana
authors.initials: I
authors.lastname: Carnevali
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliani
authors.forename: Alessio
authors.initials: A
authors.lastname: Fornasin
authors.forename: Marco
authors.initials: M
authors.lastname: Agostini
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestro
authors.forename: Daniela
authors.initials: D
authors.lastname: Barana
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Viel
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D045647:DNA Glycosylases / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007558:Italy; D009154:Mutation; D044465:White People / Q000235:genetics*
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase