UNC13A

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UNC13A
Identifiers
AliasesUNC13A, Munc13-1, unc-13 homolog A (C. elegans), unc-13 homolog A
External IDsOMIM: 609894 MGI: 3051532 HomoloGene: 11279 GeneCards: UNC13A
Orthologs
SpeciesHumanMouse
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 MbChr 8: 72.08 – 72.12 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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:

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

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000130477 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b "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.
  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.
  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.
  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.
  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.

Further reading

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

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