Altered neuronal physiology, development, and function associated with a common chromosome 15 duplication involving...

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• Copy number variants (CNVs) impacting nervous system genes are linked to neuropsychiatric disorders.
• Duplicative CNVs often show variable penetrance compared to deletions.
• Chromosome 15q13.3 duplications involving CHRNA7 are associated with neuropsychiatric conditions of unknown penetrance variability.

Purpose of the Study:

• To investigate the cellular basis for variable phenotypic expressivity in individuals with 15q13.3 duplications.
• To model neuropsychiatric disease using induced pluripotent stem cells (iPSCs) derived from affected and unaffected family members.

Main Methods:

• Generated iPSC models from a family with a 15q13.3 duplication (affected son and unaffected mother).
• Differentiated iPSCs into cortical excitatory and inhibitory neurons for cellular phenotype analysis.
• Assessed neural progenitor proliferation, neuronal differentiation, maturation, migration, endoplasmic reticulum (ER) stress, and gene expression.

Main Results:

• Affected proband-derived neurons showed impaired differentiation, maturation, migration, and increased ER stress, unlike the unaffected mother or controls.
• Pharmacological agents partially rescued neuronal migration deficits and ER stress in the affected model.
• Both affected and unaffected carrier neurons exhibited increased firing and cholinergic activity, linked to CHRNA7.
• Gene expression analysis revealed distinct dysregulation in the affected proband and compensatory upregulation in the unaffected mother.

Conclusions:

• Identified diagnosis-specific cellular phenotypes and shared functional anomalies in 15q13.3 duplication carriers.
• Findings suggest CHRNA7 duplication impacts neuronal function and contributes to variable disease penetrance.
• Pharmacological rescue of some anomalies indicates potential therapeutic strategies for related CNV disorders.