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Mutations in NR2F2 can induce atrioventricular defects, LV outflow tract obstruction
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Inherited defects affecting the heart at birth are the most common of all birth defects in the world. About 5% of congenital heart defects are due to atrioventricular septal defects and the prevalence is about 0.4% per 1,000 live births.
Atrioventricular septal defects can be part of a syndrome involving other organs such as Down syndrome, in which 46% of patients have atrioventricular septal defects. Understanding why the remaining 54% do not have atrioventricular septal defects could provide important information on cardiac development. Syndromic atrioventricular septal defect is only a small part of atrioventricular septal defects; most occur without any other organ involvement. A few genes have been associated with nonsyndromic atrioventricular septal defects, including CRELD1 (MIN 607170), ALK2 (MIM 102576), TBX5 (MIM 601620) and GATA 4 (MIM 680576); however, these genes have not been proven to have a causal association.
Using EXOME sequencing, Al Turki and colleagues discovered that mutations in the NR2F2 gene, which encodes a transcriptional factor, may exhibit either a phenotype of atrioventricular septal defects or left ventricular outflow tract obstruction, depending on which function of the NR2F2 gene is affected by the mutation.
Challenge of identification
Until recently, the technique to identify genes responsible for rare single-gene disorders was that of genetic linkage analysis. This required finding a pedigree of two or more generations having individuals affected with the disorder of interest. The DNA of unaffected and affected individuals within the pedigree are genotyped with DNA markers of known chromosomal location. Those markers segregating with affected individuals only would indicate they are in close physical proximity to the gene responsible for the disorder. The DNA region demarcated by the biomarkers can then be cloned and the mutation detected by sequencing. Since these atrioventricular septal defects are rare and penetrance is often not 100%, finding two- or three-generation pedigrees with individuals having atrioventricular septal defects in each generation has been a major limitation.
Robert Roberts
Mutations responsible for single-gene disorders usually occur in protein-coding regions of the genome, referred to as exons, which exit the nucleus as templates for protein synthesis and make up less than 2% of the genome. The remaining 98% of DNA regions do not code for protein, remain in the nucleus and are referred to as introns.
Major developments
Two major developments have occurred that have transformed our approach to identifying genes responsible for rare single-gene disorders. In the past 10 years, the price of DNA sequencing has decreased 1,000,000-fold and the rate of sequencing has increased 1,000-fold. It is estimated there are about 180,000 exons in the human genome, which, when combined, is referred to as the EXOME. The new approach to get around the lack of access to pedigrees with rare inherited defects is to sequence the EXOME in unrelated affected individuals. However, since EXOME sequencing will identify many causal and benign mutations, ascertaining which mutation is the cause of the defect can be difficult.
In their study, Al Turki and colleagues took a very clever and targeted approach of sequencing the EXOME of 13 parent-offspring trios and a large cohort of 112 unrelated individuals with nonsyndromic atrioventricular septal defects. They identified five rare missense mutations in the NR2F2 gene by EXOME sequencing. In three additional families, mutations in NR2F2 gene were discovered segregating with congenital cardiac defects: one consisting of a chromosomal translocation in an individual with coarctation of the aorta; the second was a three-base pair duplication associated with tetralogy of Fallot; and the third was a de novo substitution associated with hypoplastic left heart syndrome.
The NR2F2 gene belongs to the steroid/thyroid hormone receptor superfamily of transcription factors. The function of transcriptional factors is to promote or inhibit the expression of other genes. In the case of the NR2F2 gene, it encodes for a protein which, under certain circumstances, promotes expression of genes and, under other conditions, inhibits the expression of genes. Studies in mice showed mutations induced in NR2F2 are associated with a spectrum of cardiac developmental disorders ranging from hypoplasia to atrioventricular septal defects. The investigators performed several in vitro studies to determine the function of NR2F2. The combination of the results of the functional studies together with previous published animal studies on NR2F2 have led to several conclusions related to the formation of atrioventricular septal defects and cardiac development.
NR2F2: A dosage-sensitive gene regulator
Missense mutations that leave the gene promotion function of NR2F2 intact induce dysfunction leading to improper development of the endocardial cushion, resulting in atrioventricular septal defects without other abnormalities. In contrast, the mutations that disrupt the function of NR2F2 to inhibit promotion are associated with LV outflow tract abnormalities such as tetralogy of Fallot or aortic dysplasia. Interestingly, it is also recognized that NR2F2 acts as an environmentally responsive factor by mediating the effect of high glucose and retinoic acid levels. Insulin and glucose are known to decrease the expression of NR2F2. Thus, NR2F2 can be added to the short list of dosage-sensitive gene regulators such as TBX5, TBX1, NKX 2-5 and GATA 4, which have been shown, when mutated, to alter cardiac development and induce several cardiac phenotypes consisting of atrioventricular septal defects and outflow tract abnormalities.
Reference:
Al Turki S, et al. Am J Hum Genet. 2014;doi:10.1016/j.ajhg.2014.03.007.
For more information:
Robert Roberts, MD, MACC, FRSC, FRCPC, is former president and CEO of the University of Ottawa Heart Institute, professor of medicine at the University of Ottawa and director of the Ruddy Canadian Cardiovascular Genetics Center. He also is a member of the Cardiology Today Editorial Board. Roberts can be reached at bobrobertsx2@gmail.com.
Disclosure: Roberts reports no relevant financial disclosures.