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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The Rac1 guanine exchange factor Kalirin-7 is a key regulator of dendritic spine morphology, LTP and dendritic arborization. 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 within the catalytic domain of Kalirin-7, and results in a robust reduction in Kalirin-7 Rac1 Guanosine exchange factor activity. In contrast to wild type Kalirin-7, the E1577K mutant failed to drive dendritic arborization, spine density, NMDAr targeting to, and activity within, spines. Together these results indicate that reduced Rac1-GEF activity as result of E1577K mutation impairs neuroarchitecture, connectivity and NMDAr activity, and is a likely contributor to impaired neurodevelopment in a patient with developmental delay.

Original languageEnglish (US)
Article number994513
JournalFrontiers in Molecular Neuroscience
Volume15
DOIs
StatePublished - Dec 1 2022

Keywords

  • NMDAr
  • developmental delay
  • neurodevelopment
  • neuron
  • spine

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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