At Children's Mercy, James E.
O'Brien Jr., MD, FACS, Co-Director of the Ward Family Heart Center
and Associate Professor of Surgery, UMKC School of Medicine, and
Douglas Bittel, PhD, Associate Professor in the Section of Genetics
Research, are following up on their recent investigation into
idiopathic, congenital heart defects and delving further into the
intricate relationship between, and possible causal effects of,
small nucleolar RNA (snoRNA) expression and conotruncal
The team's initial findings were
published in the June 2012 issue of Circulation: Cardiovascular
Dr. O'Brien explains that the high
incidence and difficulty in managing certain groups of patients led
to his early interest in researching the defects.
"We hoped to identify some causative
genetic defect or subtype among this group of patients so we could
manage them in a specific way, using a directed therapy," Dr.
The two studied tissue of the
affected right ventricular myocardium from 16 infants with
nonsyndromic tetralogy of Fallot (TOF) without a chromosome 22q11.2
deletion to see if there were any remnants of gene expression that
might point to what went wrong early in gestation2. [Bittel et al.
2011] They found splicing variants in 51 percent of genes critical
for cardiac development.1
"Our interest was: What happened to
the expression of the messenger RNA in the affected tissue? And,
that is what led to the more recent work dealing with noncoding RNA
(ncRNA)," Dr. Bittel says.
They found that a specific group of
snoRNAs was down regulated in children with TOF, and that the
irregularity was consistent in every case studied. Drs. Bittel and
O'Brien reason that the well-documented role snoRNAs play in
regulation of the spliceosome in the yeast model might also apply
to the development of sporadic heart defects in humans.
"It has a pretty dramatic impact on
the way genes get processed, and that variation in processing is
much more prominent in the regulatory networks that control heart
development," says Dr. Bittel.
Continuing this line of research,
Dr. Bittel has created primary cell lines from the myocardium of
patients with TOF. He then altered the expression of a small,
targeted number of the snoRNAs. Results have shown a trend toward a
return to normal splicing patterns.
The researchers are collaborating
with Naoya Kenmochi, PhD, Frontier Science Research Center,
University of Miyazaki, Japan, who is using the zebrafish model to
alter these snoRNAs.
Dr. Bittel says, "When you target
those snoRNAs in zebrafish, they also get heart defects."
Those results support the theory
about the role snoRNAs play in conotruncal defects.
"That is the very first step in
demonstrating that alterations in snoRNA levels may contribute to
heart defects," Dr. Bittel continues. Misregulation of snoRNAS and
its culpability in other disorders, including cancer and
inflammation, is an area of growing interest among researchers, and
Drs. O'Brien and Bittel posit that there are more hidden links to
be discovered among this class of ncRNAS. Dr. O'Brien adds, "After
looking at the genetic expression, we may be able to identify
subgroups that would benefit from different therapeutic
interventions and more directed therapies."
The ongoing research into the
relationship between ncRNAs and congenital heart defects is
furthering the understanding of the etiology of heart disorders,
and thus ultimately is geared toward improving patients'
1. Noncoding RNA expression in
myocardium from infants with tetralogy of Fallot; Circ
Cardiovasc Genet. 2012 Jun; O'Brien
JE Jr, Kibiryeva N, Zhou XG, Marshall JA, Lofland GK,
Artman M, Chen J, Bittel DC.
2. Bittel DC, Butler MG, Kibiryeva
N, Marshall JA, Chen J, Lofland GK, O'Brien JE, Jr. 2011.
Gene expression in cardiac tissues
from infants with idiopathic conotruncal defects. BMC
Med Genomics 4(1):1.