[12][14][15] The KALRN gene, has been linked to multiple neurological disorders both through large exome and genome sequencing efforts, as well as post mortem and clinical studies.

Another, found within the second GEF domain, is predicted to be highly deleterious to RhoA-GEF activity and likely affects the function of kalirin9 and 12 isoforms early in neuronal development.

[20] Several intronic variants have been associated with addiction and were found to alter the function of brain regions responsible for reward anticipation.

Numerous missense mutations in KALRN have been identified in exome sequencing studies of schizophrenia cohorts [25] that are predicted to be deleterious to protein function.

[38][39][40][41] These effects are regulated by protein-protein interactions and post-translational modifications within the non-catalytic domains, and have been shown to exert control over kalirin subcellular targeting and activation.

The importance of KALRN in neurodevelopment is supported by knockout animal models that display profound deficiencies in multiple behavioral tasks.

[13][46] The generation of a kalirin7 specific knockout animal model revealed similar deficits in spine density,[46][47] suggesting a central role of kalirin7 in regulating neuronal connectivity.

Both full and kalirin7 specific knockout animals show decreased anxiety-like behavior and impaired contextual fear learning.

Multiple isoforms, arising from alternate splicing and promoter usage, display varying tissue and developmental expression.

[44] It is likely this subcellular distribution is vital to kalirin7 function, as this isoform exerts control dendritic spine density and synaptic plasticity.