Functional null mutations in the gonosomal homologue gene TBL1Y are associated with non-syndromic coarctation of the aorta

Journal article


Publication Details

Author(s): Tagariello A, Breuer C, Birkner Y, Schmidt S, Koch AM, Cesnjevar R, Rueffer A, Dittrich S, Schneider H, Winterpacht A, Sticht H, Doetsch J, Toka O
Journal: Current Molecular Medicine
Publication year: 2012
Volume: 12
Journal issue: 2
Pages range: 199-205
ISSN: 1566-5240


Abstract


In patients with congenital heart defects, chromosomal anomalies are 100 times more frequent than in control subjects. Coarctation of the aorta can be detected in 15-20% of patients with Ullrich-Turner syndrome. By extensively reviewing literature involving breakpoint analysis of gonosomal deletions in Ullrich- Turner syndrome patients with and without coarctation of the aorta, we identified several gonosomal homolgous gene pairs of interest. Four of these homologous gene pairs were investigated by standard DNA sequencing in a cohort of 83 patients with non-syndromic coarctation of the aorta. Subsequently stability of mutant RNA and protein was analyzed to verify functional relevance of detected mutations. We identified two unreported missense mutations in Exon 8 (p.D69H) and 9 (p.R176W) of TBL1Y. Bioinformatic analysis and 3D modelling predicted that both mutations lead to TBL1Y loss of function. In RT-PCR and Western blot analyses of HEK293 cells transfected with a vector carrying the full-length TBL1Y (wild-type and mutant), we documented the predicted protein instability by showing protein decay for both mutant proteins. TBL1Y is similar to its gonosomal homologue, TBL1X, and its autosomal homologue, TBLR1, on chromosome 3. Both genes are part of co-repressor machineries and required for transcriptional activation by transcription factors that involve CtBP1/2, which contributes to Notch signaling. Several studies have shown that Notch signalling is important for proper development of the left ventricular outflow tract. Our findings suggest that TBL1Y is involved in the genesis of non-syndromic coarctation of the aorta.



FAU Authors / FAU Editors

Cesnjevar, Robert Prof. Dr.
Kinderherzchirurgische Abteilung in der Herzchirurgischen Klinik
Dittrich, Sven Prof. Dr.
Professur für Kinderkardiologie
Koch, Anna Maria
Kinderherzchirurgische Abteilung in der Herzchirurgischen Klinik
Sticht, Heinrich Prof. Dr.
Professur für Bioinformatik
Winterpacht, Andreas Prof. Dr.
Professur für Humangenetik


External institutions with authors

Universität Köln


How to cite

APA:
Tagariello, A., Breuer, C., Birkner, Y., Schmidt, S., Koch, A.M., Cesnjevar, R.,... Toka, O. (2012). Functional null mutations in the gonosomal homologue gene TBL1Y are associated with non-syndromic coarctation of the aorta. Current Molecular Medicine, 12(2), 199-205. https://dx.doi.org/10.2174/156652412798889027

MLA:
Tagariello, Andreas, et al. "Functional null mutations in the gonosomal homologue gene TBL1Y are associated with non-syndromic coarctation of the aorta." Current Molecular Medicine 12.2 (2012): 199-205.

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Last updated on 2018-05-10 at 02:30