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

Theron A. Russell, Katherine D. Blizinsky, Derin J. Cobia, Michael E. Cahill, Zhong Xie, Robert A. Sweet, Jubao Duan, Pablo V. Gejman, Lei Wang, John G. Csernansky and Peter Penzes ()
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Theron A. Russell: Northwestern University Feinberg School of Medicine
Katherine D. Blizinsky: Northwestern University Feinberg School of Medicine
Derin J. Cobia: Northwestern University Feinberg School of Medicine
Michael E. Cahill: Northwestern University Feinberg School of Medicine
Zhong Xie: Northwestern University Feinberg School of Medicine
Robert A. Sweet: University of Pittsburgh School of Medicine
Jubao Duan: University of Chicago
Pablo V. Gejman: University of Chicago
Lei Wang: Northwestern University Feinberg School of Medicine
John G. Csernansky: Northwestern University Feinberg School of Medicine
Peter Penzes: Northwestern University Feinberg School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-8

Abstract: Abstract Dendritic spine pathology is a key feature of several neuropsychiatric disorders. The Rac1 guanine nucleotide exchange factor kalirin-7 is critical for spine morphogenesis on cortical pyramidal neurons. Here we identify a rare coding variant in the KALRN gene region that encodes the catalytic domain, in a schizophrenia patient and his sibling with major depressive disorder. The D1338N substitution significantly diminished the protein’s ability to catalyse the activation of Rac1. Contrary to wild-type kalirin-7, kalirin-7-D1338N failed to increase spine size and density. Both subjects carrying the polymorphism displayed reduced cortical volume in the superior temporal sulcus (STS), a region implicated in schizophrenia. Consistent with this, mice with reduced kalirin expression showed reduced neuropil volume in the rodent homologue of the STS. These data suggest that single amino acid changes in proteins involved in dendritic spine function can have significant effects on the structure and function of the cerebral cortex.

Date: 2014
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DOI: 10.1038/ncomms5858

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