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

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.

KALRN: A central regulator of synaptic function and synaptopathies.

The synaptic regulator, kalirin, plays a key role in synaptic plasticity and formation of dendritic arbors and spines. Dysregulation of the KALRN gene has been linked to various neurological disorders, including autism spectrum disorder, Alzheimer's disease, schizophrenia, addiction and intellectual disabilities. Both genetic and molecular studies highlight the importance of normal KALRN expression for healthy neurodevelopment and function. This review aims to give an in-depth analysis of the structure and molecular mechanisms of kalirin function, particularly within the brain. These data are correlated to genetic evidence of patient mutations within KALRN and animal models of Kalrn that together give insight into the manner in which this gene may be involved in neurodevelopment and the etiology of disease. The emerging links to human disease from post-mortem, genome wide association (GWAS) and exome sequencing studies are examined to highlight the disease relevance of kalirin, particularly in neurodevelopmental diseases. Finally, we will discuss efforts to pharmacologically regulate kalirin protein activity and the implications of such endeavors for the treatment of human disease. As multiple disease states arise from deregulated synapse formation and altered KALRN expression and function, therapeutics may be developed to provide control over KALRN activity and thus synapse dysregulation. As such, a detailed understanding of how kalirin regulates neuronal development, and the manner in which kalirin dysfunction promotes neurological disease, may support KALRN as a valuable therapeutic avenue for future pharmacological intervention.