An extra human chromosome 21 reduces mlc-2a expression in chimeric mice and Down syndrome.
An extra copy of human chromosome 21 (Chr 21) causes Down syndrome (DS), which is characterized by mental retardation and congenital heart disease (CHD). Chimeric mice containing Chr 21 also exhibit phenotypic traits of DS including CHD. In this study, to identify genes contributing to DS phenotypes, we compared the overall protein expression patterns in hearts of Chr 21 chimeras and wild type mice by two-dimensional electrophoresis. The endogenous mouse atrial specific isoform of myosin light chain-2 (mlc-2a) protein was remarkably downregulated in the hearts of chimeric mice. We also confirmed that the human MLC-2A protein level was significantly lower in a human DS neonate heart, as compared to that of a normal control. Since mouse mlc-2a is involved in heart morphogenesis, our data suggest that the downregulation of this gene plays a crucial role in the CHD observed in DS. The dosage imbalance of Chr 21 has a trans-acting effect which lowers the expression of other genes encoded elsewhere in the genome.
Nishigaki
Ryuichi
R
Department of Human Genome Science, Life Sciences Division, Graduate School of Medicine, Tottori University, Nishimachi 86, Yonago, Tottori 683-8503, Japan.
Shinohara
Tokuyuki
T
Toda
Tosifusa
T
Omori
Akira
A
Ichinose
Sachiyo
S
Itoh
Masayuki
M
Shirayoshi
Yasuaki
Y
Kurimasa
Akihiro
A
Oshimura
Mitsuo
M
D000818:Animals; D024722:Cardiac Myosins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002678:Chimera; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D015180:Electrophoresis, Gel, Two-Dimensional; D018628:Gene Dosage; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis
D018994:Myosin Light Chains; D012333:RNA, Messenger; C107184:myosin light chain 2; D024722:Cardiac Myosins