KALRN

Official Full Name

kalirin RhoGEF kinase

Organism

Homo sapiens

GeneID

8997

Background

Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with the huntingtin-associated protein 1, which is a huntingtin binding protein that may function in vesicle trafficking. [provided by RefSeq, Apr 2016]

Synonyms

DUO; CHD5; DUET; TRAD; CHDS5; HAPIP; KALNC2; ARHGEF24;

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Detailed Information

Recent Research

KALRN is the causative gene for the autosomal recessive phenotype in monogenic intellectual disability family. Furthermore, KALRN whose variants are associated with coronary artery disease (CAD), located on the 3q13 chromosomal region, a susceptible region for CAD. KALRN genetic variation is link to CAD and ischemic stroke. KALRN is an extremely large gene and has 60 exons with multiple promoters, spanning about 620 kb. One identified novel homozygous missense variant in KALRN was predicted to be pathogenic by all pathogenicity prediction software. KALRN is a GTP-exchange factor protein with a reported role in cytoskeletal remodeling and dendritic spine formation in neurons. Some reports show that mice with ablation of Kalrn exhibit age-dependent functional deficits and behavioral phenotypes. Some reports on the KALRN gene showed that SNP rs9289231 in the first intron of kalirin alternative transcripts is associated with early-onset CAD. There is a rare coding variant in the KALRN gene region that encodes the catalytic domain, in a schizophrenia patient and his sibling with major depressive disorder.

Lack of Kalrn expression in POMC cells closely mimicked the effects of global Kalrn knockout on anxiety-like behavior and passive avoidance conditioning without causing the other deficits noted in Kalrn knockout mice. Some reports show that mice with reduced kalirin expression showed reduced neuropil volume in the rodent homolog of the STS. Kalirin-7and the rodent Kalrn gene, is the most highly expressed kalirin protein isoform in the adult rodent. Some reports show that Kalrn knockout mice display a preadolescent reduction in cortical dendritic spine number and reduced dendritic complexity, as well as deficits in working memory that emerge in adolescence. KALRN has been associated with schizophrenia risk. Mice lacking the kalrn gene show reduced cortical thickness, suggesting a potential link between molecular and cellular alterations and macroscopic neuromorphological phenotypes. Total knockout of the Kalrn gene in mice leads to reduced cortical thickness, as measured in the frontal cortex. Kalrn heterozygotes exhibited a significant reduction in neuropil area as compared to wildtypes.

Mice unable to express any of the isoforms of Kalrn in cells that produce POMC at any time during development (POMC cells) exhibited reduced anxiety-like behavior and reduced acquisition of passive avoidance behavior, along with sex-specific alteration in the corticosterone response to restraint stress. The human KALRN gene encompasses several functional domains and generates multiple isoforms; KALRN has been implicated in cardiovascular disease, ischemic stroke, schizophrenia, Alzheimer’s disease and attention deficit hyperactivity disorder. The rodent Kalrn gene gives rise to similar developmentally regulated and functionally distinct isoforms. KALRN strongly associates with early-onset coronary artery disease and atherosclerosis and plays an important role in stroke patients. Some studies indicate that the two SNPs at intronic regions may affect KALRN expression or lead to alternative splicing of kalirin protein, generating isoforms. KALRN has an association with complications and subtypes of ischemic stroke. The association of known polymorphisms of the kalirin-coding gene, KALRN, with common disease in different populations is controversial.

References:

Dang M, et al. KALRN Rare and Common Variants and Susceptibility to Ischemic Stroke in Chinese Han Population. Neuromolecular Medicine, 2015, 17(3):241-250.
Mandela P, et al. Elimination of Kalrn, expression in POMC cells reduces anxiety-like behavior and contextual fear learning. Hormones & Behavior, 2014, 66(2):430-438.
Russell T A, et al. A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness. Nature Communications, 2014, 5(5):4858-4858.
Mofarrah M, et al. Association of KALRN, ADIPOQ, and FTO gene polymorphism in type 2 diabetic patients with coronary artery disease: possible predisposing markers. Coronary Artery Disease, 2016, 27(6):490.
Makrythanasis P, et al. Exome sequencing discloses KALRN homozygous variant as likely cause of intellectual disability and short stature in a consanguineous pedigree. Human Genomics, 2016, 10(1):1-7.

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