New research in mice suggests a gene that modifies chromatin may contribute to the wide variability in severity of velo-cardio-facial(VCF)/DiGeorge syndrome.
That gene, MOZ, interacts with the gene Tbx1, which influences heart and aortic arch development and is involved in the disorder, write researchers from the Walter and Eliza Hall Institute in Melbourne and University College London in Developmental Cell (Voss et al., 2012). The disorder is also known as 22q11 deletion, as most cases of the syndrome are caused by a 22q11 microdeletion. Tbx1 is located in the 22q11 region and a small proportion of cases of the syndrome result from heterozygous deletion of Tbx1 in otherwise intact 22q11 regions.
Manifestations of the velo-cardio-facial/DiGeorge syndrome—which affects 1 in 4,000 people—can vary widely even among affected members of the same family and identical twins. Symptoms include heart and aortic arch defects present from birth, cleft palate, a facial phenotype, decreased platelets, feeding difficulties, and hearingloss. Many of these children have intellectual disabilities, and are at increased risk of developing mental illnesses, particularly schizophrenia, later in life. Variability in the severity of symptoms among patients with the 22q11 deletion syndrome has long been a topic of research.
MOZ makes a profound difference in normal embryonic development and cellular processes, says Anne Voss, PhD, head of the Development and Cancer Division at The Walter and Eliza Hall Institute of Medical Research in Victoria, Australia. MOZ modifies chromatin by making chemical marks that govern when, and where, genes switch on and off. Her team found that MOZ can mediate effects of Tbx1 in mice.
Because phenotypes of mice with Tbx1 deletion are very similar to those in humans with deletions in the same gene, her findings may someday be relevant to the treatment of children with this disorder, Dr. Voss says. Her research group is interested in chromatin modifiers including MOZ because they have the potential to integrate environmental effects and alter expression levels of key regulators of aortic arch and heart development.
The researchers report results in 33 mice that lacked MOZ, which expresses an enzyme that acetylates conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyllysine. These mice had symptoms that mirror those of DiGeorge syndrome in humans.
The researchers showed that the MOZ complex occupies the Tbx1 locus, promoting its expression and histone 3 lysine 9 acetylation. The study also showed that MOZ plays a role in development of the heart, pharynx, and palate. Defects in these structures are common in 22q11 deletion syndrome.
Importantly, the paper implies that MOZ is involved in the effect of retinoic acid, a natural form of vitamin A in retinol, used to treat acne in humans. For some time, researchers have known that increased maternal intake of prescription level doses of isotretinoin (vitamin A) during pregnancy can cause a constellation of birth defects similar to those of the DiGeorge anomoly (Guillonneau et al., 1997).
Voss's research team saw more severe anomalies in mice with homozygous MOZ mutations and in heterozygous MOZ mutants that were exposed to an oversupply of retinoic acid or had an additional Tbx1 haploinsuffiency. Meanwhile, the team found that inserting a Tbx1 transgene into a mouse genome lacking MOZ reduced the occurrence of heart defects in MOZ mutants.
“Researchers should consider MOZ activity as a factor causing variability in DiGeorge syndrome and 22q11 deletion syndrome,” Dr. Voss says.
Voss's findings are important because they point to a mechanism at play in more severe disease, says Paula Goldenberg, MD, Assistant Professor in the University of Cincinnati School of Medicine's Department of Pediatrics in Ohio. “Histone acetylates like MOZ may have something to do with it,” Dr. Goldenberg says. “If we know the mechanism for more severe disease, we may determine for parents whether or not their children might be at risk for the more severe phenotype.”
Previous research has found that common mutations in Tbx1 do not explain variable cardiovascular expression in more than 1,000 patients with 22q11 deletion. Instead, studies have implicated the existence of modifiers in other genes on 22q11, and elsewhere in the genome (Guo et al., 2011). In contrast, Dr. Voss's paper suggests new pathways to examine, says Bernice Morrow, PhD, Director of the Division of Translational Genetics at Yeshiva University's Albert Einstein College of Medicine in New York.
“The connection between MOZ and retinoic acid—that a MOZ mutation sensitizes an embryo to retinoic acid—is as interesting as the interactionbetweenMOZ and Tbx1 because it's an environmental factor,” adds Dr. Morrow. “People want to know: Could alterations in genes or their expression increase sensitivity to environmental exposure? That's what this paper implies. We all know environment can play a role in congenital heart disease. This paper connects MOZ activity to the environment.”
However, any future research that better explains the link would need to be proven in humans to have any clinical relevance, Dr. Morrow points out. “This paper won't help a child with DiGeorge syndrome right now, but it's a tool for understanding how environmental signals can regulate genes,” she adds.