Copy Number Variation, Microdeletion, and Disease

Paul Volden, PhD
Friday, September 16th, 2016
Copy number variations (CNVs) are duplications and deletions to large (~5kb-5mb) genomic regions found in varying degrees within the human population. These duplications and deletions significantly contribute to human genetic diversity and can dramatically affect gene-dosage.

Brain Connections Neurons
Recently, pathologic and highly-penetrant CNVs have been identified in patients with neurodevelopmental and psychiatric disorders. The microdeletion at chromosome location 15q13.3 is one example. This CNV can result in a range of disorders, including autism spectrum disorder, epilepsy, schizophrenia, and learning disabilities.

For neurological disorders, the underlying genetics are multifactorial and incompletely penetrant, with phenotypes that often overlap. This makes them much more difficult to study via model systems. Rodent models of human disease can be powerful tools for elucidating disease mechanisms, but complex neurological disorders, like those associated with the 15q13.3 microdeletion, are far more challenging to model.

Recently, researchers began characterizing a novel mouse model created to shed light on the human 15q13.3 microdeletion. Most rodent models of human disease are produced with minimal gene modifications to help confer a narrow phenotypic scope. Conversely, the 15q13.3 microdeletion mouse (Df(h15q13)/+) carries a hemizygous deletion of an entire genomic region, orthologous to the 15q13.3 microdeletion in humans, containing six genes.

Modeling the Human 15q13.3 Microdeletion

In several recent investigations, characterizations of Df(h15q13)/+ mice have unmasked neuronal and behavioral alterations related to epilepsy and schizophrenia. For example, Df(h15q13)/+ mice display deficits in auditory processing, impaired long-term spatial reference memory, and an increased propensity to develop myoclonic seizures.

Interestingly, mice homozygous for the 15q13.3 microdeletion are viable and have pronounced phenotypes. Some of the phenotypes include altered seizure susceptibility, autistic behavior-related phenotypes, and auditory sensory processing deficits. Shared phenotypes between hemizygous (Df(h15q13)/+) mice and homozygous mice were more pronounced in the homozygotes, suggesting a gene dosage influence.

Reversal of a Schizophrenia-Associated Phenotype in Df(h15q13)/+ Mice

In a study published in the July 2016 issue of European Neuropsychopharmacology, scientists compared Df(h15q13)/+ mice to wild-type mice using functional MRI. In Df(h15q13)/+ mice a hyperconnectivity pattern was observed that appeared to replicate an established schizophrenia-associated connectivity phenotype.

Df(h15q13)/+ mice carry a hemizygous deletion of 6 genes (Fan1, Mtmr10, Trpm1, Klf13, Otud7a and Chrna7). Among these, CHRNA7, which encodes nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the predominant genes within the deletion contributing to human neuropsychiatric phenotypes. Working from this lead, investigators hypothesized that pharmacologic modulation of nAChA7Rs might normalize the hyperconnectivity pattern observed in the Df(h15q13)/+ mice.

The researchers tested the effects of Lu AF58801, a novel selective and brain penetrant allosteric activator of nAChA7Rs. Df(h15q13)/+ mice received an intraperitoneal injection of Lu AF58801 or saline and underwent fMRI imaging sessions. In the animals that received the pharmacologic nAChA7Rs allosteric activator, hyperconnectivity was normalized, and the most striking effects were observed in the brain regions expressing nACha7Rs.

Prior studies have shown that pharmacological stimulation of nAChA7Rs restores auditory gating deficits in rodent schizophrenia models and activates regions of the brain similar to conventional antipsychotics. The scientists concluded that the hyperconnectivity normalizing effects they observed with Lu AF58801 may underlie the apparent benefits of nAChA7R stimulation on cognition and auditory deficits.

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