title: Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome.
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.
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology, University of Strasbourg, Strasbourg, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Sellier
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Vicki J
authors.initials: VJ
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Dandekar
authors.affiliation: Department of Public Health Sciences, UC Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Blythe
authors.initials: B
authors.lastname: Durbin-Johnson
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology, University of Strasbourg, Strasbourg, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
authors.affiliation: MIND Institute, UC Davis Medical Center, Sacramento, California, United States of America; Department of Neurology, UC Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Ander
authors.affiliation: MIND Institute, UC Davis Medical Center, Sacramento, California, United States of America; Department of Neurology, UC Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Sharp
authors.affiliation: MIND Institute, UC Davis Medical Center, Sacramento, California, United States of America; Department of Pediatrics, UC Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Angkustsiri
authors.affiliation: MIND Institute, UC Davis Medical Center, Sacramento, California, United States of America; Department of Psychiatry, UC Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Simon
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California, United States of America; MIND Institute, UC Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
mesh_terms: D000293:Adolescent; D002648:Child; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D004062:DiGeorge Syndrome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: C474043:DGCR8 protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins
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