title: Alternative approach to a heavy weight problem.
abstract: Obesity is reaching epidemic proportions in developed countries and represents a significant risk factor for hypertension, heart disease, diabetes, and dyslipidemia. Splicing mutations constitute at least 14% of disease-causing mutations, thus implicating polymorphisms that affect splicing as likely candidates for disease susceptibility. A recent study suggested that genes associated with obesity were significantly enriched for rare nucleotide variants. Here, we examined these variants and revealed that they are located near splice junctions and tend to affect exonic splicing regulatory sequences. We also show that the majority of the exons that harbor these SNPs are constitutively spliced, yet they exhibit weak splice sites, typical to alternatively spliced exons, and are hence suboptimal for recognition by the splicing machinery and prone to become alternatively spliced. Using ex vivo assays, we tested a few representative variants and show that they indeed affect splicing by causing a shift from a constitutive to an alternative pattern, suggesting a possible link between extreme body mass index and abnormal splicing patterns.
authors: Department of Human Genetics and Molecular Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
authors: Amir
authors: A
authors: Goren
authors: Eddo
authors: E
authors: Kim
authors: Maayan
authors: M
authors: Amit
authors: Ron
authors: R
authors: Bochner
authors: Galit
authors: G
authors: Lev-Maor
authors: Nadav
authors: N
authors: Ahituv
authors: Gil
authors: G
authors: Ast
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D015992:Body Mass Index; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D005091:Exons / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers