title: Functional null mutations in the gonosomal homologue gene TBL1Y are associated with non-syndromic coarctation of the aorta.
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.
authors.affiliation: Institute of Human Genetics, University of Erlangen, Schwabachanlage 10, Erlangen, D-91054, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Tagariello
authors.forename: C
authors.initials: C
authors.lastname: Breuer
authors.forename: Y
authors.initials: Y
authors.lastname: Birkner
authors.forename: S
authors.initials: S
authors.lastname: Schmidt
authors.forename: A M
authors.initials: AM
authors.lastname: Koch
authors.forename: R
authors.initials: R
authors.lastname: Cesnjevar
authors.forename: A
authors.initials: A
authors.lastname: Ruffer
authors.forename: S
authors.initials: S
authors.lastname: Dittrich
authors.forename: H
authors.initials: H
authors.lastname: Schneider
authors.forename: A
authors.initials: A
authors.lastname: Winterpacht
authors.forename: H
authors.initials: H
authors.lastname: Sticht
authors.forename: J
authors.initials: J
authors.lastname: Dotsch
authors.forename: O
authors.initials: O
authors.lastname: Toka
mesh_terms: D000293:Adolescent; D000328:Adult; D001017:Aortic Coarctation / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D055550:Protein Stability; D017433:Protein Structure, Secondary; D012730:Sex Chromosomes; D015293:Transducin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C485612:TBL1Y protein, human; D015293:Transducin