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Inversion region for hypertension and brachydactyly on chromosome 12p features multiple splicing and noncoding RNA

Item Type:Article
Title:Inversion region for hypertension and brachydactyly on chromosome 12p features multiple splicing and noncoding RNA
Creators Name:Baehring, S. and Kann, M. and Neuenfeld, Y. and Gong, M. and Chitayat, D. and Toka, H.R. and Toka, O. and Plessis, G. and Maass, P. and Rauch, A. and Aydin, A. and Luft, F.C.
Abstract:Autosomal-dominant hypertension and brachydactyly (Online Mendelian Inheritance in Man 112410) is a prototype-translational research project. We used interphase fluorescent in situ hybridization and discovered complex rearrangements on chromosome 12p in 5 families but elucidated a common inverted region in the linkage interval. The inversion contains no known gene. However, we found 5 expressed sequence tags in databases. We used 5'- and 3'-Rapid Amplification of cDNA Ends PCR for elongation of the transcripts in phenotype-relevant tissue (fetal aorta, fetal brain, and fetal cartilage). We detected tissue-specific multiple splicing with different exon usage of 32 exons in the gene-related structure. These different transcripts lack both open reading frames and Kozak sequences. In vitro transcription/translation experiments did not identify any peptide-related molecules. We then performed quantitative RT-PCR to test for differential expression of the various spliced transcripts in the total fibroblast RNA of affected and nonaffected Turkish family members. Skin fibroblasts of affected individuals have a significantly increased proliferation rate compared with nonaffected individuals. Ten of 12 spliced exon combinations representing all of the spliced variants do not show a significantly different RNA expression rate. However, 2 RT-PCR products are exclusively expressed in nonaffected individuals. Both reverse transcription amplicons share 1 exon. This result is surprising because of the autosomal-dominant mode of inheritance of the trait. RNA secondary prediction of this single exon results in a stable stem-loop structure known to be essential for microRNA processing. We are pursuing the possibility of microRNA expression in affected patients that leads to complete down regulation of a spliced transcript.
Keywords:Hypertension, Genetics, Mendelian, Chromosomal rearrangements, Translational research
Publisher:American Heart Association
Page Range:426-431
Date:February 2008
Official Publication:https://doi.org/10.1161/HYPERTENSIONAHA.107.101774
PubMed:View item in PubMed

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