Mutational analysis of the human MESP1 gene in patients with congenital heart disease reveals a highly variable sequence in exon 1.
MESP1 represents an essential transcription factor to guarantee coordinated cardiac development. The expression of MESP1 is thought to be the first sign that a cell has been committed to the cardiac lineage. We analyzed the coding sequence of MESP1 in 215 patients with congenital heart disease. Our results show that the sequence of exon 1 is highly variable with up to seven alterations in individual samples. Five base pair positions (c.157_G>C A53P, rs6496598; c.174_A>C P58P, rs28377352; c.182_T>G L61R, rs28368490; c.669_C>G F223L, rs2305440; c.687_T>G P229P, rs2305441) are particularly variable. In almost half of the samples a 12 base pair insertion after position 55 (c.165_166insGTGCCGAGCCCC P55insVPSP, rs71934166) coding for VPSP was detected which was strongly correlated with the appearance of further amino acid changes (c.157_G>C A53P, c.182_T>G L61R, c.669_C>G F223L). Two missense mutations (c.33_G>C E11D, rs190259690; c.528_A>T T176S) were detected in two patients but were absent in the controls. The assessment of the biological activity of altered MESP1 proteins in a luciferase reporter assay showed an enhanced activity of the c.33_G>C E11D mutation and a reduction of the insertion without an accompanying change of c.182_T>G L61R. The modified biological properties of mutated MESP1 proteins might be associated with the appearance of certain pathological phenotypes of congenital heart disease.
Department of Cardiovascular Surgery, Division of Experimental Surgery, German Heart Center Munich, Technische Universität München, Munich Heart Alliance, Munich, Germany. Electronic address: lahm@dhm.mhn.de.
Harald
H
Lahm
Marcus-André
MA
Deutsch
Martina
M
Dreßen
Stefanie
S
Doppler
Astrid
A
Werner
Jürgen
J
Hörer
Julie
J
Cleuziou
Christian
C
Schreiber
Johannes
J
Böhm
Karl-Ludwig
KL
Laugwitz
Rüdiger
R
Lange
Markus
M
Krane
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide
D051792:Basic Helix-Loop-Helix Proteins; C000589015:MESP1 protein, human
Congenital heart disease; DNA sequencing; Luciferase activity; MESP1; Mutation; Single nucleotide polymorphism