Dysregulation of DGCR6 and DGCR6L: psychopathological outcomes in chromosome 22q11.2 deletion syndrome

D Chakraborty,K Schoch,A J Bernal,E H Ip,R L Jirtle,V Shashi,M S Keshavan,T D Howard,S R Hooper

doi:10.1038/tp.2012.31

Abstract

Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans. It is typified by highly variable symptoms, which might be explained by epigenetic regulation of genes in the interval. Using computational algorithms, our laboratory previously predicted that DiGeorge critical region 6 (DGCR6), which lies within the deletion interval, is imprinted in humans. Expression and epigenetic regulation of this gene have not, however, been examined in 22q11DS subjects. The purpose of this study was to determine if the expression levels of DGCR6 and its duplicate copy DGCR6L in 22q11DS subjects are associated with the parent-of-origin of the deletion and childhood psychopathologies. Our investigation showed no evidence of parent-of-origin-related differences in expression of both DGCR6 and DGCR6L. However, we found that the variability in DGCR6 expression was significantly greater in 22q11DS children than in age and gender-matched control individuals. Children with 22q11DS who had anxiety disorders had significantly lower DGCR6 expression, especially in subjects with the deletion on the maternal chromosome, despite the lack of imprinting. Our findings indicate that epigenetic mechanisms other than imprinting contribute to the dysregulation of these genes and the associated childhood psychopathologies observed in individuals with 22q11DS. Further studies are now needed to test the usefulness of DGCR6 and DGCR6L expression and alterations in the epigenome at these loci in predicting childhood anxiety and associated adult-onset pathologies in 22q11DS subjects.

Highlights

Chromosome 22q11.2 deletion syndrome (22q11DS), known as velocardiofacial or DiGeorge syndrome, is a common hemizygous microdeletion syndrome occurring in 1 in 1600– 4000 live births.[1]
We examined the expression of DGCR6L as it is a duplicate of DGCR6 and its expression and association with the neuropsychological findings in children with 22q11DS could be similar
Our aims were to determine the expression patterns of DGCR6 and DGCR6L in subjects with 22q11DS compared with age- and gender-matched control subjects

Summary

Introduction

Chromosome 22q11.2 deletion syndrome (22q11DS), known as velocardiofacial or DiGeorge syndrome, is a common hemizygous microdeletion syndrome occurring in 1 in 1600– 4000 live births.[1] Approximately 85% of subjects carry a 3-Mb deletion (Figure 1). A minority with a smaller 1.5-Mb deletion still show all the characteristics of the disorder, delimiting this as the 22q11DS minimal DiGeorge critical region (DGCR). Individuals with 22q11DS display variable conotruncal heart defects, atypical facial features, velopharyngeal insufficiency, and cognitive and psychiatric abnormalities.[2,3,4]. The cognitive abnormalities include borderline IQ to mild intellectual impairment, poor sustained attention, executive dysfunction and visual–spatial skills.[5,6,7,8] Minor psychiatric manifestations are common during childhood, with as many as 50% experiencing an anxiety disorder and/or ADHD.[9,10,11,12,13] In late adolescence and early adulthood, major psychotic disorders, such as schizophrenia, bipolar illness and major depression, develop in 25–40% of the affected individuals.[14,15,16] These cognitive and psychiatric manifestations vary in their severity and frequency

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