Novel mutations A210G and L15Q TBX5 gene in the patients with
non-syndromic congenital defects of the heart septal
Abstract
The TBX5 transcription factor plays an important role during
morphogenesis and development of the heart. Mutations in this gene often
lead to Holt-Oram syndrome (HOS). This study identified mutations in
patients with non-syndromic congenital heart defects (CHD). Screening
for mutations TBX5 gene in non-syndromic CHD, including 100 patients
with a septal defect and 50 healthy subjects as controls were performed
by the technique of high-resolution melt (HRM). Exons were sequenced for
samples that showed HRM curve differences compared to controls.
Structural stability and pathogenic potential of mutated protein were
evaluated by bioinformatics analysis. HRM curve analysis showed that the
curves of three samples deviated from the curves of controls. Sequencing
showed three heterozygous missense mutations including two novel
mutations NM_000192.3:c.44T>G, (p.L15Q),
NM_000192.3c.629C>G (p.A210G) and a known mutation
NM_000192.3:c.331G>T (p.D111Y). The PolyPhen-2 software
predicted the p.D111Y and p.A210G substitutions to be disease-causing
and p.L15Q as possibly benign, while protein structural stability
analysis by MUpro and DynaMut suggested that these mutations reduce
stability and increase the flexibility of the protein. This study
presents two novel missense mutations within the TBX5 gene that may be
causal for non-syndrome CHD.