Cause of Brain Defects Linked to Genetic Deletion Identified

May 14, 2008

Deletion of a small chromosomal region in mice equivalent to the 22q11.2 deletion in humans, which is associated with behavioral and cognitive defects and an increased risk of schizophrenia, is associated with defects in the processing of microRNAs and cognitive and behavioral deficits, according to research published online May 11 in Nature Genetics.

WEDNESDAY, May 14 (HealthDay News) -- Deletion of a small chromosomal region in mice equivalent to the 22q11.2 deletion in humans, which is associated with behavioral and cognitive defects and an increased risk of schizophrenia, is associated with defects in the processing of microRNAs (miRNAs) and cognitive and behavioral deficits, according to research published online May 11 in Nature Genetics.

Kimberly L. Stark, Ph.D., from Columbia University in New York City, and colleagues analyzed alterations in mice engineered to have a hemizygous 1.3-Mb deletion at the locus equivalent to the human 22q11.2 locus.

The researchers found that the mice were hyperactive and had cognitive defects. Transcriptional profiling in the hippocampus and prefrontal cortex showed that miRNA-related transcripts were consistently upregulated. Mice heterozygous for a gene disrupted by the deletion, Dgcr8, which encodes a double-stranded RNA-binding protein that is an important component of the "microprocessor complex" involved in the maturation of miRNAs, had defects in miRNA biogenesis and behavioral and cognitive defects.

"In summary, our results indicate that abnormal processing of miRNAs contributes to the behavioral and neuronal deficits associated with the human 22q11.2 microdeletion," Stark and colleagues conclude. "DGCR8 haploinsufficiency, although not solely responsible, is very likely to interact with haploinsufficiency of other 22q11.2 genes to produce the synaptic alterations as well as the cognitive and behavioral defects associated with the 22q11.2 microdeletions."

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