By Deborah Levenson RESEARCH UPDATE ASPECT OF FAULTY BRAIN DEVELOPMENT IN 22Q11 DELETION SYNDROME SHOWN Genetic deletions disrupt ability of interneurons to control brain circuit activity eletions in the 22q11 gene associated Dwith autism and other behavioral diseases disrupt cellular and molecular mechanisms that ensure normal development of interneurons, according to recent research. 22q11 deletion syndrome affects 1 out of every 2,000-4,000 newborns. In addition to autism and other behavioral conditions, children with the disorder may also suffer from cleft palate, heart defects, immune system deficits, growth delay, kidney problems, hearing loss, and endocrine issues. Writing in the Proceedings of the National Academy of Science, researchers at George Washington University in Washington, DC, show that deletions © Beneda Miroslav \ Shutterstock.com Miroslav © Beneda in 22q11.2 disrupt cortical circuit Deletions in the 22q11 gene, which prevent interneurons from moving properly into the cortex and development in a mouse model. Early cause a change in brain circuitry, have been associated with heart defects and autism in children. generated parvalbumin-expressing interneurons—which have relatively don’t get to the right spot, so the proper deletions of the region on chromosome short axons and inhibit activity by other brain circuitry never develops,” says 16 that is analogous to the 1.5 megabases neurons—are made in the right numbers David R. Lynch, MD, PhD, Professor of missing in patients with 22q11 deletion at their birthplace outside of the cortex, but Neurology at University of Pennsylvania syndrome, except for four genes. don’t move properly into the cortex where in Philadelphia and attending physician at Researchers used a genetic marker to they are needed to control circuit activity. Children’s Hospital of Philadelphia. “It’s identify interneurons that travel to the That’s mainly because of diminished not a degenerative process.” cerebral cortex and distinguish them from expression of activity of a key regulatory The team’s more recent findings those that don’t. They used microarrays pathway for migration, the Cxcr4 cytokine are an important step forward, says lead on the interneurons that don’t make the receptor, the researchers conclude in their author Anthony-Samuel LaMantia, trip to discern differences in Cxcr4 protein most recent study (Meechan et al., 2012). PhD, Director of the GWU Institute for expression in those cells. In previous research, Meechan et Biomedical Science. “We’ve identified a Since Cxcr4 was reduced in migrating al found that projection neurons—key clear cellular target that causes change in interneurons, the researchers discerned cortical neurons with longer axons that brain circuitry,” LaMantia notes. “Now, that diminished Cxcr4 altered interneuron go to more distant regions of the brain with a mouse model and genetic tools, we migration in the developing mouse cortex. and have neurotransmitters causing more can look more at developmental processes “Thus, diminished 22q11.2 gene dosage activity —were made in the right numbers that occur before the brain is built and the disrupts cortical circuit development by at their birthplace outside of the cortex behavior happens.” modifying a critical molecular signaling in a 22q11.2 mouse model (Meechan et pathway via Cxcr4 that regulates cortical al., 2009). This research showed that in The Study interneuron migration and placement,” cases of 22q11 deletion, “interneurons The researchers examined mice with write Meechan et al. © 2013 Wiley Periodicals, Inc. ix RESEARCH UPDATE CONTINUED A Piece of the Puzzle identify a target for drug intervention. are to understanding why the majority The more recent paper is important “Once we know why interneurons are have learning problems, and a significant because it identifies differences in the in the wrong place, we can use that number have mental health issues,” adds brains of patients with 22q11 deletion that information and mouse models to see if Dr. McPherson. can lead to behavioral and mental health drugs modify aberrant circuitry that drive disorders, says Dr. Lynch. The findings behavioral changes,” says Dr. LaMantia. References “may eventually help identify circuitry That knowledge could benefit human Meechan DW, Tucker ES, Maynard TM, LaMantia AS. abnormality that we could selectively patients with 22q11 deletion, he adds. 2012. Cxcr4 regulation of interneuron migration intervene upon,” he adds. The most recent findings by Meechan is disrupted in 22q11.2 deletion syndrome. Proc The researchers are working toward et al are important because the research Natl Acad Sci USA 109(45):18601-18606. that goal. Next, they will try to find out “tells us the problem is with how the Meechan DW, Tucker ES, Maynard TM, LaMantia how faulty signaling by Cxcr4 causes brain develops to begin with, not AS. 2009. Diminished dosage of 22q11 genes affected interneurons to lose their way damage that happens afterwards,” notes disrupts neurogenesis and cortical development and how that affects the building of brain Elizabeth McPherson, MD, Director in a mouse model of 22q11 deletion/ structures. Dr. LaMantia says another of Medical Genetics at the Marshfield DiGeorge syndrome. Proc Natl Acad Sci USA aspect of research should address “whether Clinic, headquartered in Marshfield, 106(38):16434–16445. Cxrc4-mediated change is specifically Wisconsin. “The more we understand correlated with changes in behavior.” about what’s different in the brains of DOI 10.1002/ajmg.a.35899 Answers to these questions could people with 22q11 deletion, the closer we © 2013 Wiley Periodicals, Inc. SCREENING UPDATE GENETIC DEFECTS BEHIND FRAGILE X-RELATED DISORDERS MORE COMMON Researchers find the incidence of one type of FMR1 allele double its previous estimate in males utations in the fragile X mental from 14,207 male and female infants at from primary ovarian insufficiency. Mretardation 1 (FMR1) gene are three university medical centers. Older male and female carriers may more common than previously thought, Typically, people who have one copy, develop a tremor and ataxia syndrome according to recently published data from or allele, of a gene for a genetic disease called fragile X-associated tremor/ataxia a pilot newborn screening program. do not suffer ill effects. But those who syndrome (FXTAS). Both gray-zone and FMR1 mutations, the most common carry aberrant FMR1 alleles may be at premutation alleles are unstable and genetic cause of intellectual disabilities risk of developing certain disorders. may possibly expand to full mutations in and autism, occur in the sequence of the Children with a full fragile X mutation— future generations [Tassone, et al., 2013; nucleotides cytosine-guanine-guanine which encompasses more than 200 CGG Fernandez-Carvajal et al., 2009]. (CGG) in the promoter region of the repeats—have fragile X syndrome (FXS), “The premutation is common and FMR1 gene. FMR1 expresses fragile X which is associated with more severe can be inexpensively identified with mental retardation protein (FMRP), disabilities. The researchers did not PCR that could be used in newborn which is required for normal neural estimate the prevalence of full mutations, screening,” says lead author Flora Tassone, development. but they did estimate incidence of PhD, a biochemist and investigator at Writing in the December 20, 2012 premutation and gray-zone alleles, which UC Davis’ Medical Investigation of issue of Genome Medicine, researchers encompass smaller numbers of CGG Neurodevelopmental Disorders (MIND) at the University of California at Davis repeats and may cause fragile X-related Institute. estimated the incidence of one type of medical, neurological, and psychiatric FMR1 allele, the permutation, at 1 in problems. Premutation alleles with 55 to Findings 400 for males, double that of previous 199 repeats are associated with autism, Prior to the latest research by Tassone et al, estimates [Tassone et al., 2012]. Its attention deficit hyperactivity disorder, no large scale population-based screening incidence among girls was about half depression, and anxiety. Adult female for FXS in both males and females across that figure, they found. Researchers based premutation carriers and some gray- the entire spectrum of fragile X mutations their estimates on pilot polymerase chain zone carriers—who have FMR1 alleles had been conducted in the U.S. Tassone reaction (PCR) testing of blood spots with 45 to 54 CGG repeats—may suffer et al identified the overall prevalence of x.