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News and Features Researching the Link Between Congenital Heart Defects and Noncoding RNA

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 defects.

The team's initial findings were published in the June 2012 issue of Circulation: Cardiovascular Genetics.

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. O'Brien adds.

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' prognosis.

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.

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