UNC13A

UNC13A
Identifiers
Aliases	UNC13A , Munc13-1, unc-13 homolog A (C. elegans), unc-13 homolog A
External IDs	OMIM: 609894; MGI: 3051532; HomoloGene: 11279; GeneCards: UNC13A; OMA:UNC13A - orthologs
Gene location (Human) Chr. Chromosome 19 (human) [1] Band 19p13.11 Start 17,601,336 bp [1] End 17,688,365 bp [1]
Gene location (Mouse) Chr. Chromosome 8 (mouse) [2] Band 8|8 B3.3 Start 72,077,061 bp [2] End 72,124,401 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right hemisphere of cerebellum beta cell olfactory bulb right frontal lobe prefrontal cortex superior frontal gyrus middle temporal gyrus dorsolateral prefrontal cortex Brodmann area 9 pituitary gland Top expressed in superior frontal gyrus dentate gyrus of hippocampal formation granule cell primary visual cortex primary motor cortex neural layer of retina cerebellar cortex piriform cortex prefrontal cortex hippocampus proper subiculum More reference expression data BioGPS n/a
Gene ontology Molecular function syntaxin-1 binding metal ion binding diacylglycerol binding calmodulin binding calcium ion binding phospholipid binding Cellular component cytoplasm membrane neuromuscular junction plasma membrane synapse axon cell junction neuron projection presynaptic membrane presynapse terminal bouton calyx of Held presynaptic active zone glutamatergic synapse synaptic vesicle membrane presynaptic active zone cytoplasmic component Biological process cell differentiation intracellular signal transduction synaptic vesicle docking synaptic transmission, glutamatergic regulation of short-term neuronal synaptic plasticity positive regulation of neurotransmitter secretion amyloid-beta metabolic process neuromuscular junction development positive regulation of dendrite extension regulation of synaptic transmission, glutamatergic innervation synaptic vesicle maturation neurotransmitter secretion exocytosis chemical synaptic transmission synaptic vesicle exocytosis synaptic vesicle priming positive regulation of synaptic plasticity positive regulation of glutamate receptor signaling pathway regulation of amyloid precursor protein catabolic process presynaptic dense core vesicle exocytosis dense core granule priming Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23025 382018 Ensembl ENSG00000130477 ENSMUSG00000034799 UniProt Q9UPW8 Q4KUS2 RefSeq (mRNA) NM_001080421 NM_001387021 NM_001387022 NM_001387023 NM_001029873 RefSeq (protein) NP_001073890 NP_001025044 Location (UCSC) Chr 19: 17.6 – 17.69 Mb Chr 8: 72.08 – 72.12 Mb PubMed search [3] [4]
Wikidata
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Unc-13 homolog A (C. elegans) is a protein that in humans is encoded by the UNC13A gene ^[5] and in mice by the Munc13-1 gene. ^[6]

Function

This gene encodes a member of the UNC13 family. ^[5] UNC13A plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. It is involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool. In Drosophila melanogaster , the protein has been shown to define the vesicle release site by regulating the coupling distance between synaptic vesicles and calcium channels in cooperation with another isoform, UNC13B. ^[7] It is particularly important in most glutamatergic-mediated synapses as well as GABA-mediated synapses. It plays a role in dendrite formation by melanocytes and in secretory granule priming in insulin secretion. ^[8]

Protein structure

Several conserved domains have been found in UNC13A. These conserved domains include three C2 domains. One C2 domain is centrally located, another is at the carboxyl end, and there is a third. In addition, there is one C1 domain, as well as Munc13 homology domains 1 (MHD1) and 2 (MHD2). ^{[8] [9]}

Subcellular location

UNC13A is localized to the active zone of presynaptic density. It is translocated to the plasma membrane in response to phorbol ester binding. ^[8]

Interaction

UNC13A has been shown to interact with:

• STX1A, ^[8]
• STX1B1, ^[8]
• DOC2A, ^[8]
• BSN, ^[8]
• RIMS1, ^[8]
• RIMS2, ^[8]
• ERC2, ^[8] and
• RAB3A. ^[8]

Clinical significance

Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis. ^{[10] [11] [12] [13]} This single nucleotide polymorphism has been discovered on chromosome 19. This variation of the single nucleotide involving UNC13A has also been implicated in frontotemporal dementia (FTD). Pathology of TDP-43 in both ALS and FTD results in a cryptic exon being expressed in UNC13A, which is exercerbated by the single nucleotide polymorphisms associated with ALS and FTD risk. ^{[14] [15] [16]} This gene has also been associated with Alzheimer's disease (AD). ^[17]

References

1. GRCh38: Ensembl release 89: ENSG00000130477 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000034799 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Unc-13 homolog A (Homo Sapiens)".
6. "Entrez Gene: Unc-13 homolog A (Mus musculus)".
7. Böhme MA, Beis C, Reddy-Alla S, Reynolds E, Mampell MM, Grasskamp AT, et al. (October 2016). "Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling". Nature Neuroscience. 19 (10): 1311–1320. doi:10.1038/nn.4364. hdl: 11858/00-001M-0000-002B-2236-2 . PMID   27526206. S2CID   8897877.
8. "UNC13A - Protein unc-13 homolog A - Homo sapiens (Human) - UNC13A gene & protein". www.uniprot.org.
9. "NCBI Conserved Domain Search". www.ncbi.nlm.nih.gov. Retrieved 2016-05-06.
10. van Es MA, Veldink JH, Saris CG, Blauw HM, van Vught PW, Birve A, et al. (October 2009). "Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis". Nature Genetics. 41 (10): 1083–1087. doi:10.1038/ng.442. PMID   19734901. S2CID   8659710.
11. Bosco DA, Landers JE (December 2010). "Genetic determinants of amyotrophic lateral sclerosis as therapeutic targets". CNS & Neurological Disorders Drug Targets. 9 (6): 779–790. doi:10.2174/187152710793237494. PMID   20942785.
12. Su XW, Broach JR, Connor JR, Gerhard GS, Simmons Z (June 2014). "Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research". Muscle & Nerve. 49 (6): 786–803. doi:10.1002/mus.24198. PMID   24488689. S2CID   38375893.
13. Finsterer J, Burgunder JM (February 2014). "Recent progress in the genetics of motor neuron disease". European Journal of Medical Genetics. 57 (2–3): 103–112. doi: 10.1016/j.ejmg.2014.01.002 . PMID   24503148.
14. Ma XR, Prudencio M, Koike Y, Vatsavayai SC, Kim G, Harbinski F, et al. (March 2022). "TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A". Nature. 603 (7899): 124–130. Bibcode:2022Natur.603..124M. doi:10.1038/s41586-022-04424-7. PMC   8891019 . PMID   35197626.
15. Brown AL, Wilkins OG, Keuss MJ, Hill SE, Zanovello M, Lee WC, et al. (March 2022). "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A". Nature. 603 (7899): 131–137. Bibcode:2022Natur.603..131B. doi:10.1038/s41586-022-04436-3. PMC   8891020 . PMID   35197628.
16. Diekstra FP, Van Deerlin VM, van Swieten JC, Al-Chalabi A, Ludolph AC, Weishaupt JH, et al. (July 2014). "C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis". Annals of Neurology. 76 (1): 120–133. doi:10.1002/ana.24198. PMC   4137231 . PMID   24931836.
17. Hartlage-Rübsamen M, Waniek A, Roßner S (February 2013). "Munc13 genotype regulates secretory amyloid precursor protein processing via postsynaptic glutamate receptors". International Journal of Developmental Neuroscience. 31 (1): 36–45. doi:10.1016/j.ijdevneu.2012.10.001. PMID   23070049. S2CID   28216850.

Further reading

• Augustin I, Rosenmund C, Südhof TC, Brose N (July 1999). "Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles". Nature. 400 (6743): 457–461. Bibcode:1999Natur.400..457A. doi:10.1038/22768. PMID   10440375. S2CID   4364774.
• Betz A, Ashery U, Rickmann M, Augustin I, Neher E, Südhof TC, et al. (July 1998). "Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release". Neuron. 21 (1): 123–136. doi:10.1016/s0896-6273(00)80520-6. hdl: 11858/00-001M-0000-0012-FC62-6 . PMID   9697857. S2CID   15707959.
• Betz A, Thakur P, Junge HJ, Ashery U, Rhee JS, Scheuss V, et al. (April 2001). "Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming". Neuron. 30 (1): 183–196. doi:10.1016/s0896-6273(01)00272-0. hdl: 11858/00-001M-0000-0012-F596-C . PMID   11343654. S2CID   155875.
• Huang CC, Yang DM, Lin CC, Kao LS (October 2011). "Involvement of Rab3A in vesicle priming during exocytosis: interaction with Munc13-1 and Munc18-1". Traffic. 12 (10): 1356–1370. doi: 10.1111/j.1600-0854.2011.01237.x . PMID   21689256.
• Koch H, Hofmann K, Brose N (July 2000). "Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform". The Biochemical Journal. 349 (Pt 1): 247–253. doi:10.1042/0264-6021:3490247. PMC   1221144 . PMID   10861235.
• Lavi A, Sheinin A, Shapira R, Zelmanoff D, Ashery U (September 2014). "DOC2B and Munc13-1 differentially regulate neuronal network activity". Cerebral Cortex. 24 (9): 2309–2323. doi:10.1093/cercor/bht081. PMC   4128701 . PMID   23537531.
• Ohtsuka T, Takao-Rikitsu E, Inoue E, Inoue M, Takeuchi M, Matsubara K, et al. (August 2002). "Cast: a novel protein of the cytomatrix at the active zone of synapses that forms a ternary complex with RIM1 and munc13-1". The Journal of Cell Biology. 158 (3): 577–590. doi:10.1083/jcb.200202083. PMC   2173811 . PMID   12163476.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.