Kalirin, also known as Huntingtin-associated protein-interacting protein (HAPIP), protein duo (DUO), or serine/threonine-protein kinase with Dbl- and pleckstrin homology domain, is a protein that in humans is encoded by the KALRN gene. Kalirin was first identified in 1997 as a protein interacting with huntingtin-associated protein 1. Is also known to play an important role in nerve growth and axonal development.

Kalirin is a member of the Dbl family of proteins and is a Rho guanine nucleotide exchange factor.

It is named after the multiple-handed Hindu goddess Kali for its ability to interact with numerous other proteins. Kalirin's other name, DUO, comes from the fact that it is 98% identical to rat DUO protein and 80.6% identical to a human protein named TRIO. Unlike TRIO, which is expressed in numerous tissues, Kalirin isoforms are mainly found in the brain.

Several isoforms of Kalirin are produced through alternative splicing. One of the isoforms, Kalirin-7, was found to be necessary for the remodeling of synapses in mature cortical neurons and is thought to be important in the development of schizophrenia, as demonstrated by adolescent development of schizophrenia-like symptoms in kalirin knockout mice. Alzheimer's disease may also be linked to kalirin-7.

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.

Several mutations within KALRN have been linked to neurological disease. In autism spectrum disorder, a frameshift mutation was found that is likely to lead to transcript decay, and heterozygosity. 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. A patient harboring a homozygous mutation in kalirin's spectrin repeat domain was found to have severe intellectual disability, and both truncating and missense mutations have been identified in patients with developmental delay. Several intronic variants have been associated with addiction and were found to alter the function of brain regions responsible for reward anticipation. This link to addiction is supported by animal models, where loss of kalirin results in altered cocaine self-administration and synaptic and expression changes in response to cocaine. Perhaps the most compelling genetic links are between kalirin and schizophrenia. Numerous missense mutations in KALRN have been identified in exome sequencing studies of schizophrenia cohorts that are predicted to be deleterious to protein function.

Neuronal studies have provided insight into the mechanisms of some missense mutations, particularly within the GEF domains of KALRN. A mutation found within the Rac-GEF domain was found to induce strong reductions in Rac activation, neuronal branching, and spine density. These effects were mirrored by mutations in the RhoA-GEF domain, producing similar neuronal deficits, but by promoting RhoA-GEF activity. In addition to exome sequencing, post-mortem studies have consistently found alterations in kalirin transcript levels within the brain further supporting a role for kalirin in the etiology of schizophrenia.

In addition to neurodevelopmental disorders, kalirin has been found to be underexpressed in the post-mortem Alzheimer's brain. This loss of kalirin expression was recapitulated in animal models of Alzheimer's disease. Moreover, introduction of kalirin7 into culture or animal models of Alzheimer's disease was able to rescue synaptic and behavioral deficits, suggesting an important role for kalirin in regulating synapse loss and cognitive impairment in Alzheimer's disease.