Identification and characterization of human <i>KALRN</i> mRNA and Kalirin protein isoforms

Kalirin is a multidomain protein with important roles in neurite outgrowth, and synaptic spine formation and remodeling. Genetic and pathophysiological links with various neuropsychiatric disorders associated with synaptic dysfunction and cognitive impairment have sparked interest in its potential as a pharmacological target. Multiple Kalirin proteoforms are detected in the adult human brain, yet we know little about the diversity of the transcripts that encode them or their tissue profiles. Here, we characterized full-length KALRN transcripts expressed in the adult human frontal lobe and hippocampus using rapid amplification of complementary DNA (cDNA) ends and nanopore long-read sequencing. For comparison with non-neural tissue, we also analyzed KALRN transcripts in the aorta. Multiple novel isoforms were identified and were largely similar between the two brain regions analyzed. Alternative splicing in the brain results in preferential inclusion of exon 37, which encodes 32 amino acids upstream of the second guanine nucleotide exchange factor (GEF) domain. Structural modeling predicts that a subset of these amino acids forms a conserved alpha helix. Although deletion of these amino acids had little effect on GEF activity, it did alter Kalirin-induced neurite outgrowth suggesting that this brain-enriched splicing event may be important for neural function. These data indicate that alternative splicing is potentially important for regulating Kalirin actions in the human brain.

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Publication Details

Journal
Cerebral Cortex
Published
2024-12-01
DOI
https://doi.org/10.1093/cercor/bhae470
Citations
1
Primary Topic
Signaling Pathways in Disease
Type
article
Field-Weighted Citation Impact
0.23

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article

Identification and characterization of human KALRN mRNA and Kalirin protein isoforms

Klaus D. Bornemann, Wilfried Haerty, Edward Drydale, Arne W. Mould et al.
1 citations
Cerebral Cortex
Signaling Pathways in Disease
0.23
article

Identification and characterization of human KALRN mRNA and Kalirin protein isoforms

Klaus D. Bornemann, Wilfried Haerty, Edward Drydale, Arne W. Mould, James Bancroft, Elizabeth M. Tunbridge, Paul J. Harrison, Nicola Hall, Paul E. Brennan, Bastian Hengerer, Annette von Delft, David J. Wright, R.D. Pinnock
article en
1 citations

Abstract

Kalirin is a multidomain protein with important roles in neurite outgrowth, and synaptic spine formation and remodeling. Genetic and pathophysiological links with various neuropsychiatric disorders associated with synaptic dysfunction and cognitive impairment have sparked interest in its potential as a pharmacological target. Multiple Kalirin proteoforms are detected in the adult human brain, yet we know little about the diversity of the transcripts that encode them or their tissue profiles. Here, we characterized full-length KALRN transcripts expressed in the adult human frontal lobe and hippocampus using rapid amplification of complementary DNA (cDNA) ends and nanopore long-read sequencing. For comparison with non-neural tissue, we also analyzed KALRN transcripts in the aorta. Multiple novel isoforms were identified and were largely similar between the two brain regions analyzed. Alternative splicing in the brain results in preferential inclusion of exon 37, which encodes 32 amino acids upstream of the second guanine nucleotide exchange factor (GEF) domain. Structural modeling predicts that a subset of these amino acids forms a conserved alpha helix. Although deletion of these amino acids had little effect on GEF activity, it did alter Kalirin-induced neurite outgrowth suggesting that this brain-enriched splicing event may be important for neural function. These data indicate that alternative splicing is potentially important for regulating Kalirin actions in the human brain.

Cerebral CortexVol. 34(12)
University of East Anglia (GB), Centre for Human Genetics (GB), Norwich Research Park (GB), Oxford Health NHS Foundation Trust (GB), Warneford Hospital (GB), University of Oxford (GB), Biogen (United Kingdom) (GB), Earlham Institute (GB), Boehringer Ingelheim (India) (IN), Alzheimer’s Research UK (GB)
Biogen, UK Research and Innovation, National Institute for Health and Care Research, Department of Health and Social Care, Alzheimer’s Research UK, National Institutes of Health, Biotechnology and Biological Sciences Research Council, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Common Fund
Openalex Percentile: Top 40%
Signaling Pathways in Disease
0.23
DOIOpen Access PDFOpenAlex
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