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Titolo:
A nonsense mutation in MLH1 causes exon skipping in three unrelated HNPCC families
Autore:
Stella, A; Wagner, A; Shito, K; Lipkin, SM; Watson, P; Guanti, G; Lynch, HT; Fodde, R; Liu, B;
Indirizzi:
Leiden Univ, Med Ctr, Dept Human & Clin Genet, Leiden, Netherlands Leiden Univ Leiden Netherlands Human & Clin Genet, Leiden, Netherlands Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA Univ Pittsburgh Pittsburgh PA USA 15213 st Canc, Pittsburgh, PA 15213 USA Univ Bari, DIMIMP Policlin, Sez Genet Med, I-70124 Bari, Italy Univ Bari Bari Italy I-70124 oliclin, Sez Genet Med, I-70124 Bari, Italy NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA NHGRI Bethesda MD USA 20892 Mol Biol Branch, NIH, Bethesda, MD 20892 USA Creighton Univ, Sch Med, Dept Prevent Med, Omaha, NE 68178 USA Creighton Univ Omaha NE USA 68178 , Dept Prevent Med, Omaha, NE 68178 USA
Titolo Testata:
CANCER RESEARCH
fascicolo: 19, volume: 61, anno: 2001,
pagine: 7020 - 7024
SICI:
0008-5472(20011001)61:19<7020:ANMIMC>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
NONPOLYPOSIS COLORECTAL-CANCER; MESSENGER-RNA; COLON-CANCER; GENE; HMLH1; ASSOCIATION; KINDREDS; MSH6;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Fodde, R Leiden Univ, Med Ctr, Dept Human & Clin Genet, Leiden, Netherlands Leiden Univ Leiden Netherlands Clin Genet, Leiden, Netherlands
Citazione:
A. Stella et al., "A nonsense mutation in MLH1 causes exon skipping in three unrelated HNPCC families", CANCER RES, 61(19), 2001, pp. 7020-7024

Abstract

Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 are responsible for the majority of hereditary nonpolyposis colorectal cancer (HNPCC) families. A common mutation mechanism is to disrupt MLH1 and MSH2 mRNA splicing. The disruption creates aberrant mRNAs lacking specific coding exons (exon skipping). Here, we report a novel skipping of MLH1 exon 12 caused by an AAG to TAG nonsense mutation at codon 461 in three HNPCC families of North American origins. The nonsense codon was found in a conserved haplotype in the three unrelated families and seems to represent a founder mutation. The skipping created an aberrant MLH1 mRNA transcript lacking exon 12. The effect of the codon 461 nonsense mutation on exon 12 skipping is evidenteven though it was placed in a minigene construct containing entirely different coding sequences. Notably, the effect of the nonsense mutation on exon skipping is incomplete. Accordingly, a second aberrant MLH1 transcript encompassing the nonsense codon is also produced. Whereas the latter transcript is unstable, presumably because of nonsense-mediated mRNA decay, neitherof the aberrant transcripts seems to affect the stability of wild-type MLH1 mRNA. This study demonstrates that the germ-fine nonsense mutation at codon 461 of MLH1 disrupts normal MLH1 mRNA processing, and that exon skippingunderlies pathogenesis in these HNPCC families.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 18:12:26