A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Dendritic spine pathology is a hallmark of neuropsychiatric disorders.
• Kalirin-7, a Rac1 guanine nucleotide exchange factor, is crucial for dendritic spine development in cortical neurons.

Purpose of the Study:

• To investigate the impact of a rare coding variant in the KALRN gene on kalirin-7 function and its association with neuropsychiatric disorders.
• To explore the relationship between this variant, dendritic spine morphology, and cortical structure.

Main Methods:

• Identification of a rare coding variant (D1338N) in the KALRN gene in patients with schizophrenia and major depressive disorder.
• In vitro assessment of the variant's effect on kalirin-7's catalytic activity and Rac1 activation.
• Analysis of dendritic spine size and density in relation to the variant.
• Measurement of cortical volume, specifically in the superior temporal sulcus (STS), in affected individuals and in mice with reduced kalirin expression.

Main Results:

• The D1338N substitution significantly impaired kalirin-7's ability to activate Rac1.
• Kalirin-7-D1338N failed to promote normal spine size and density, unlike its wild-type counterpart.
• Individuals carrying the variant exhibited reduced cortical volume in the STS.
• Mice with reduced kalirin expression showed diminished neuropil volume in the rodent STS homologue.

Conclusions:

• Single amino acid alterations in proteins regulating dendritic spine function can profoundly impact cerebral cortex structure and function.
• This study highlights a potential genetic link between kalirin-7 dysfunction, altered cortical morphology, and neuropsychiatric conditions like schizophrenia and major depressive disorder.