Abstract
Deletion of the 1.5–3 Mb region of chromosome 22 at locus 11.2 gives rise to the chromosome 22q11.2 deletion syndrome (22q11DS), also known as DiGeorge and Velocardiofacial Syndromes. It is the most common micro-deletion disorder in humans and one of the most common multiple malformation syndromes. The syndrome is characterized by a broad phenotype, whose characterization has expanded considerably within the last decade and includes many associated findings such as craniofacial anomalies (40%), conotruncal defects of the heart (CHD; 70–80%), hypocalcemia (20–60%), and a range of neurocognitive anomalies with high risk of schizophrenia, all with a broad phenotypic variability. These phenotypic features are believed to be the result of a change in the copy number or dosage of the genes located in the deleted region. Despite this relatively clear genetic etiology, very little is known about which genes modulate phenotypic variations in humans or if they are due to combinatorial effects of reduced dosage of multiple genes acting in concert. Here, we report on decreased expression levels of genes within the deletion region of chromosome 22, including DGCR8, in peripheral leukocytes derived from individuals with 22q11DS compared to healthy controls. Furthermore, we found dysregulated miRNA expression in individuals with 22q11DS, including miR-150, miR-194 and miR-185. We postulate this to be related to DGCR8 haploinsufficiency as DGCR8 regulates miRNA biogenesis. Importantly we demonstrate that the level of some miRNAs correlates with brain measures, CHD and thyroid abnormalities, suggesting that the dysregulated miRNAs may contribute to these phenotypes and/or represent relevant blood biomarkers of the disease in individuals with 22q11DS.
Highlights
To determine if the hemizygous deletion resulted in reduced expression of genes mapping within the deleted region, we measured the gene expression levels in peripheral blood leukocytes derived from individuals with 22q11.2 deletion syndrome (22q11DS) of the following six genes: catechol-O-methyltransferase; COMT, DiGeorge syndrome critical region gene 6; DGCR6, DiGeorge syndrome critical region gene 8; DiGeorge Critical Region Gene 8 (DGCR8), zinc finger DHHC-type containing 8; ZDHHC8, thioredoxin reductase 2; TXNRD2, and solute carrier family 25 member 1; SLC25A1 and of one gene, the Glyceraldehyde 3phosphate dehydrogenase (GAPDH) used as control
ZDHHC8 has been associated with susceptibility to schizophrenia and Mukai et al demonstrated that transfection of a ZDHHC8 carrying construct into primary hippocampal neurons of Df(16)A+/2 mice could recover dendritic spine density and growth to nearly wild type (WT) levels [45]
MiRNA Expression Levels To investigate the presence of miRNA dysregulation as a result of haploinsufficiency of the DGCR8 gene, we measured the expression of selected miRNAs in 45 individuals, 30 with 22q11DS and 15 typical developing control subjects (TD)
Summary
22q11.2 Deletion Syndrome (22q11DS) (OMIM #611867), known as DiGeorge (OMIM #188400) and Velocardiofacial (OMIM #192430) syndromes, derives from the most common chromosomal deletion associated with birth defects in humans and it is estimated to occur in 1:4000 to 1:9700 live births [1,2,3,4,5]. Gene expression levels of all genes located in the deletion region have been shown to be decreased in brains of a 22q11DS mouse model when compared to that of wild type (WT) mice [27,28,29]. It has been reported that loss of miRNAs in the neural crest (cells derived from form the pharyngeal arches in the developing embryo that eventually mature into the palate, face, and heart) lead to cardiac defects that are observed in individuals with 22q11DS [38]. We report on the decreased expression levels of several genes, including DGCR8, within the 22q deletion region in individuals with 22q11DS and compared to age matched controls. Our findings support the hypothesis that alteration of the miRNA landscape in individuals with 22q11DS contributes to the observed neuronal cell dysfunction and clinical phenotypes
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