UNC13A

{{Short description|Protein-coding gene in the species Homo sapiens}}

Unc-13 homolog A (C. elegans) is a protein that in humans is encoded by the UNC13A gene.{{cite web | title = Entrez Gene: Unc-13 homolog A (C. elegant) | url = https://www.ncbi.nlm.nih.gov/gene/23025 }}

Function

This gene encodes a member of the UNC13 family. 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.{{cite journal | vauthors = Böhme MA, Beis C, Reddy-Alla S, Reynolds E, Mampell MM, Grasskamp AT, Lützkendorf J, Bergeron DD, Driller JH, Babikir H, Göttfert F, Robinson IM, O'Kane CJ, Hell SW, Wahl MC, Stelzl U, Loll B, Walter AM, Sigrist SJ | display-authors = 6 | title = Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling | journal = Nature Neuroscience | volume = 19 | issue = 10 | pages = 1311–1320 | date = October 2016 | pmid = 27526206 | doi = 10.1038/nn.4364 | hdl = 11858/00-001M-0000-002B-2236-2 | s2cid = 8897877 | hdl-access = free }} 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.{{cite web|title=UNC13A - Protein unc-13 homolog A - Homo sapiens (Human) - UNC13A gene & protein|url=https://www.uniprot.org/uniprot/Q9UPW8|website=www.uniprot.org}}

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).{{Cite web|url=https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi?seqinput=NP_001073890.2|title=NCBI Conserved Domain Search|website=www.ncbi.nlm.nih.gov|access-date=2016-05-06}}

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.

Interaction

UNC13A has been shown to interact with:

STX1A,
STX1B1,
DOC2A,
BSN,
RIMS1,
RIMS2,
ERC2, and
RAB3A.

Clinical significance

Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis.{{cite journal | vauthors = van Es MA, Veldink JH, Saris CG, Blauw HM, van Vught PW, Birve A, Lemmens R, Schelhaas HJ, Groen EJ, Huisman MH, van der Kooi AJ, de Visser M, Dahlberg C, Estrada K, Rivadeneira F, Hofman A, Zwarts MJ, van Doormaal PT, Rujescu D, Strengman E, Giegling I, Muglia P, Tomik B, Slowik A, Uitterlinden AG, Hendrich C, Waibel S, Meyer T, Ludolph AC, Glass JD, Purcell S, Cichon S, Nöthen MM, Wichmann HE, Schreiber S, Vermeulen SH, Kiemeney LA, Wokke JH, Cronin S, McLaughlin RL, Hardiman O, Fumoto K, Pasterkamp RJ, Meininger V, Melki J, Leigh PN, Shaw CE, Landers JE, Al-Chalabi A, Brown RH, Robberecht W, Andersen PM, Ophoff RA, van den Berg LH | display-authors = 6 | title = Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis | journal = Nature Genetics | volume = 41 | issue = 10 | pages = 1083–1087 | date = October 2009 | pmid = 19734901 | doi = 10.1038/ng.442 | s2cid = 8659710 }}{{cite journal | vauthors = Bosco DA, Landers JE | title = Genetic determinants of amyotrophic lateral sclerosis as therapeutic targets | journal = CNS & Neurological Disorders Drug Targets | volume = 9 | issue = 6 | pages = 779–790 | date = December 2010 | pmid = 20942785 | doi = 10.2174/187152710793237494 }}{{cite journal | vauthors = Su XW, Broach JR, Connor JR, Gerhard GS, Simmons Z | title = Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research | journal = Muscle & Nerve | volume = 49 | issue = 6 | pages = 786–803 | date = June 2014 | pmid = 24488689 | doi = 10.1002/mus.24198 | s2cid = 38375893 }}{{cite journal | vauthors = Finsterer J, Burgunder JM | title = Recent progress in the genetics of motor neuron disease | journal = European Journal of Medical Genetics | volume = 57 | issue = 2–3 | pages = 103–112 | date = February 2014 | pmid = 24503148 | doi = 10.1016/j.ejmg.2014.01.002 | doi-access = free }} 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.{{cite journal | vauthors = Ma XR, Prudencio M, Koike Y, Vatsavayai SC, Kim G, Harbinski F, Briner A, Rodriguez CM, Guo C, Akiyama T, Schmidt HB, Cummings BB, Wyatt DW, Kurylo K, Miller G, Mekhoubad S, Sallee N, Mekonnen G, Ganser L, Rubien JD, Jansen-West K, Cook CN, Pickles S, Oskarsson B, Graff-Radford NR, Boeve BF, Knopman DS, Petersen RC, Dickson DW, Shorter J, Myong S, Green EM, Seeley WW, Petrucelli L, Gitler AD | display-authors = 6 | title = TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A | journal = Nature | volume = 603 | issue = 7899 | pages = 124–130 | date = March 2022 | pmid = 35197626 | doi = 10.1038/s41586-022-04424-7 | pmc = 8891019 | bibcode = 2022Natur.603..124M }}{{cite journal | vauthors = Brown AL, Wilkins OG, Keuss MJ, Hill SE, Zanovello M, Lee WC, Bampton A, Lee FC, Masino L, Qi YA, Bryce-Smith S, Gatt A, Hallegger M, Fagegaltier D, Phatnani H, Newcombe J, Gustavsson EK, Seddighi S, Reyes JF, Coon SL, Ramos D, Schiavo G, Fisher EM, Raj T, Secrier M, Lashley T, Ule J, Buratti E, Humphrey J, Ward ME, Fratta P | display-authors = 6 | title = TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A | journal = Nature | volume = 603 | issue = 7899 | pages = 131–137 | date = March 2022 | pmid = 35197628 | doi = 10.1038/s41586-022-04436-3 | pmc = 8891020 | bibcode = 2022Natur.603..131B }}{{cite journal | vauthors = Diekstra FP, Van Deerlin VM, van Swieten JC, Al-Chalabi A, Ludolph AC, Weishaupt JH, Hardiman O, Landers JE, Brown RH, van Es MA, Pasterkamp RJ, Koppers M, Andersen PM, Estrada K, Rivadeneira F, Hofman A, Uitterlinden AG, van Damme P, Melki J, Meininger V, Shatunov A, Shaw CE, Leigh PN, Shaw PJ, Morrison KE, Fogh I, Chiò A, Traynor BJ, Czell D, Weber M, Heutink P, de Bakker PI, Silani V, Robberecht W, van den Berg LH, Veldink JH | display-authors = 6 | title = C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis | journal = Annals of Neurology | volume = 76 | issue = 1 | pages = 120–133 | date = July 2014 | pmid = 24931836 | pmc = 4137231 | doi = 10.1002/ana.24198 }} This gene has also been associated with Alzheimer's disease (AD).{{cite journal | vauthors = Hartlage-Rübsamen M, Waniek A, Roßner S | title = Munc13 genotype regulates secretory amyloid precursor protein processing via postsynaptic glutamate receptors | journal = International Journal of Developmental Neuroscience | volume = 31 | issue = 1 | pages = 36–45 | date = February 2013 | pmid = 23070049 | doi = 10.1016/j.ijdevneu.2012.10.001 | s2cid = 28216850 }}