AUTHOR=Parnell Euan , Voorn Roos A. , Martin-de-Saavedra M. Dolores , Loizzo Daniel D. , Dos Santos Marc , Penzes Peter 

TITLE=A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 15 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.994513

DOI=10.3389/fnmol.2022.994513

ISSN=1662-5099

ABSTRACT=The Rac1 guanine exchange factor Kalirin-7 is a key regulator of dendritic spine morphology, LTP and dendritic arborization. Localizing to dendritic spines, Kalirin-7 dysfunction and genetic variation has been extensively linked to various neurodevelopmental and neurodegenerative disorders. Here we characterize a Kalirin-7 missense mutation, glu1577lys (E1577K), identified in a patient with severe developmental delay. The E1577K point mutation is located at the binding site of Kalirin-7 and the NR2B subunit of the N-methyl-D-aspartate receptor (NMDAr). This Kalirin-7 mutant showed enhanced NR2B interactions and altered localization. In contrast to wild type Kalirin-7, the E1577K mutant failed to drive dendritic arborization, spine density, and NMDAr activity within spines, alongside a robust reduction in Kalirin-7 RAC1 guanine exchange factor activity. Together these results indicate that reduced RAC-GEF activity as result of E1577K mutation impairs neuroarchitecture, connectivity and NMDAr activity, and is a likely contributor to impaired neurodevelopment and the observed developmental delay.