This Article Full Text Full Text (PDF) All Versions of this Article: 51/2/426    most recent HYPERTENSIONAHA.107.101774v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bähring, S. Articles by Luft, F. C. Search for Related Content PubMed PubMed Citation Articles by Bähring, S. Articles by Luft, F. C. Pubmed/NCBI databases Medline Plus Health Information High Blood Pressure Related Collections Cerebrovascular disease/stroke Smooth muscle proliferation and differentiation Clinical Studies CT and MRI Acute Cerebral Hemorrhage Acute Cerebral Infarction

(Hypertension. 2008;51:426.)
© 2008 American Heart Association, Inc.

Novartis Award for Hypertension Research

Inversion Region for Hypertension and Brachydactyly on Chromosome 12p Features Multiple Splicing and Noncoding RNA

Sylvia Bähring; Martin Kann; Yvette Neuenfeld; Maolian Gong; David Chitayat; Hakan R. Toka; Okan Toka; Ghislaine Plessis; Philipp Maass; Anita Rauch; Atakan Aydin; Friedrich C. Luft

From the Medical Faculty of the Charité (S.B., M.K., Y.N., M.G., H.R.T., P.M., A.A., F.C.L.), Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine, and HELIOS Klinikum Berlin-Buch, Berlin, Germany; Prenatal Diagnosis and Medical Genetics Program (D.C.), Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; Klinik für Kinder und Jugendliche (O.T.) and Institute of Human Genetics (A.R.), University Hospital Erlangen, University of Erlangen-Nürnberg, Erlangen, Germany; and the Departement Genetique et Reproduction (G.P.), Centre Hospitalier Universitaire de Caen, Caen, France.

Correspondence to Friedrich C. Luft, Max-Delbrück Center, Helmholtz-Haus, Robert-Rössle Str 10, 13125 Berlin, Germany. E-mail luft{at}charite.de

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.

Key Words: hypertension • genetics • Mendelian • chromosomal rearrangements • translational research

This article has been cited by other articles:

				M. Liang, Y. Liu, D. Mladinov, A. W. Cowley Jr., H. Trivedi, Y. Fang, X. Xu, X. Ding, and Z. Tian MicroRNA: a new frontier in kidney and blood pressure research Am J Physiol Renal Physiol, September 1, 2009; 297(3): F553 - F558. [Abstract] [Full Text] [PDF]