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(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