NEW YORK (Reuters Health) - Two different mutations apparently contribute to different types of congenital heart disease, according to reports in an advance issue of Nature Genetics, published online February 28.
Dr. J. David Brook, a geneticist at the University of Nottingham, UK, and associates screened members of a large family with dominantly inherited atrial septal defect. They identified a missense substitution in the alpha-myosin heavy chain gene (MYH6) in affected family members and obligate carriers, but not in unaffected family members or gene samples from 200 healthy unrelated individuals.
“Alpha-myosin is a structural protein expressed almost exclusively in the atrium,” Dr. Brook noted in an interview with Reuters Health.
Experiments in developing chick hearts showed that MYH6 knockdown led to absent or limited atrial septum formation, but other parts of the heart and other organs were unaffected.
“The obvious question that we now want to address is to what extent might this be relevant to sporadic congenital heart disease,” Dr. Brook said. To that end, he and his colleagues are collaborating with cardiologists in the UK to collect gene samples and test them for MYH6 gene mutations.
Meanwhile, a team led by Christine E. Seidman, at Harvard Medical School in Boston, has identified a large base-pair deletion in the transcriptional coactivator gene EYA4 that causes autosomal dominant dilated cardiomyopathy preceded by sensorineural hearing loss. EYA4 is expressed in both the heart and cochlea.
The researchers observed the deletion in EYA4 of all affected family members, while EYA4 from 300 control chromosomes appeared to be normal, they report.
To further characterize the consequences of EYA4 mutation, Dr. Seidman’s group reduced the expression of EYA4 in zebrafish embryos, which subsequently displayed ventral swelling “suggestive of cardiovascular dysfunction,” they report. They also observed ventricular wall motion abnormalities, reduced peak blood flow during cardiac systole and in some cases, blood flow from ventricle to atria.
“The primary response to Eya4 deficiency seems to be impaired cardiac function,” they conclude.
Source: Nat Genet 2005. [ Google search on this article ]
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