title: A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness.
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.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Theron A
authors.initials: TA
authors.lastname: Russell
authors.affiliation: 1] Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Blizinsky
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Derin J
authors.initials: DJ
authors.lastname: Cobia
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cahill
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xie
authors.affiliation: 1] Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA [2] Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sweet
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, Illinois 60637, USA [2] Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois 60208, USA.
authors.forename: Jubao
authors.initials: J
authors.lastname: Duan
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, Illinois 60637, USA [2] Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois 60208, USA.
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Gejman
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Csernansky
authors.affiliation: 1] Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Penzes
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D019581:Neuropil / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017422:Sequence Analysis, DNA; D035781:Siblings; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C107953:RAC1 protein, human; C503866:KALRN protein, human; D017346:Protein Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein