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)
End	17,688,365 bp
Gene location (Mouse)
Chr.	Chromosome 8 (mouse)
End	72,124,401 bp
RNA expression pattern
	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
	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
	23025
	382018
	ENSG00000130477
	ENSMUSG00000034799
	Q9UPW8
	Q4KUS2
	NM_001080421; NM_001387021; NM_001387022; NM_001387023
	NM_001029873
	NP_001073890
	NP_001025044
	Wikidata
View/Edit Human	View/Edit Mouse

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Unc-13 homolog A (C. elegans) is a protein that in humans is encoded by the UNC13A gene.^[5]

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.^[6] 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.^[7]

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).^[7]^[8]

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.^[7]

Interaction

UNC13A has been shown to interact with:

STX1A,^[7]
STX1B1,^[7]
DOC2A,^[7]
BSN,^[7]
RIMS1,^[7]
RIMS2,^[7]
ERC2,^[7] and
RAB3A.^[7]

Clinical significance

Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis.^[9]^[10]^[11]^[12] 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.^[13]^[14]^[15] This gene has also been associated with Alzheimer's disease (AD).^[16]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000130477 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000034799 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b "Entrez Gene: Unc-13 homolog A (C. elegant)".
^ 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.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k "UNC13A - Protein unc-13 homolog A - Homo sapiens (Human) - UNC13A gene & protein". www.uniprot.org.
^ "NCBI Conserved Domain Search". www.ncbi.nlm.nih.gov. Retrieved 2016-05-06.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.

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.

This article on a gene on human chromosome 19 is a stub. You can help Wikipedia by expanding it.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000130477 – Ensembl, May 2017

[refGRCm38Ensembl-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.

[entrez-5] "Entrez Gene: Unc-13 homolog A (C. elegant)".

[6] 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.

[:0-7] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k "UNC13A - Protein unc-13 homolog A - Homo sapiens (Human) - UNC13A gene & protein". www.uniprot.org.

[8] "NCBI Conserved Domain Search". www.ncbi.nlm.nih.gov. Retrieved 2016-05-06.

[9] 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.

[pmid20942785-10] 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.

[pmid24488689-11] 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.

[pmid24503148-12] 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.

[13] 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.

[14] 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.

[15] 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.

[16] 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.

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