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FLASH GENE

Symbol

TOR1A

contributors: npt/mct/pgu - updated : 19-04-2010

HGNC name	torsin family 1, member A (torsin A)
HGNC id	3098

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	11.22 kb     5 Exon(s)

regulatory sequence	Promoter
text structure	proximal minimal promoter within -191 bp with respect to the ATG codon with multiple transcription start sites, and presence of a highly conserved direct repeat of two Ets binding cores within -78 bp to -69 bp, which are transcriptional activators

MAPPING

cloned

Y

linked

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000113 5 - 2117 NP_000104 - 332 - 2009 19535332

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver       highly Nervous brain diencephalon hypothalamus       brain forebrain cerebral cortex frontal     brain limbic system hippocampus dentate gyrus     brain midbrain       Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine   Muscular striatum skeletal     Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Nervous Purkinje cell

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal endoplasmic reticulum (ER)3 signal sequence
	a 20-AA hydrophobic region followed by a conserved AAA+ (ATPases associated with a variety of cellular activities) domain (Giles 2009)
	glycosylation and potential phosphorylation sites
	hydrophobic potential membrane-spanning domain
	20-amino-acid-long hydrophobic segment remaining at the N-terminus after signal-peptide cleavage, responsible for the membrane anchoring

conjugated

GlycoP

HOMOLOGY

interspecies

ortholog to murine Tor1a

intraspecies

homolog to TOR1B, heat shock proteins and Clp proteases

Homologene

FAMILY	AAA ATPase superfamily of chaperone-like proteins
	clpA/clpB family
	torsin subfamily
	AAA+ ATPase superfamily

CATEGORY

chaperone/stress , enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,lumen
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,cytoskeleton,microtubule
	intracellular,nuclear envelope,lumen
text	mostly in endoplasmic reticulum, lesser in nuclear envelope, primarily associated with the ER and nuclear envelope (NE) compartments in cells
	found throughout the cytoplasm, neurite processes, and growth cones
	located within the lumen of the nuclear envelope (NE) and endoplasmic reticulum (ER)

basic FUNCTION	potentially involved in synaptic functioning
	having either a housekeeping function or a synaptic function
	capable of self-associating into an oligomeric complex
	may be involved in connecting the nuclear envelope to the cytoplasmic cytoskeleton
	can regulate the cellular trafficking of the dopamine transporter, as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels
	may contribute to maintain the appropriate site-directed polarization and control neurite outgrowth
	acting as an ER chaperone protein in a dynamic complex of proteins that links the NE/ER/Golgi, cytoskeleton, and translational machinery
	playing a role together with snapin (SNAPAP) in regulated exocytosis
	role in dynamic interactions between the KASH domains of nesprins and their protein partners in the lumen of the NE (nuclear enveloppe), with TOR1A influencing the localization of nesprins and associated cytoskeletal elements and affecting their role in nuclear and cell movement
	has a regulatory role in vesicle recycling
	may function as a molecular chaperone
	play a role in several cellular processes, including dopaminergic neurotransmission, nuclear envelope organization and dynamics, and protein trafficking

CELLULAR PROCESS

protein, post translation, folding

PHYSIOLOGICAL PROCESS

cellular trafficking transport

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP binding

protein	interacting with LAP1 and LULL1
	association between TOR1A and nesprin-3, which spans the outer nuclear membrane (ONM) of the nuclear envelope and links it to vimentin via plectin in fibroblasts
	interacting with KLHL14 (disruption of the KLHL14- torsinA interaction by mutation could contribute to the pathophysiology of DYT1 dystonia)

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

DYT1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation       GAG mutation, in early-onset recurrent major depression, independently of motor manifestations of dystonia

Susceptibility

to sporadic idiopathic dystonia

Variant & Polymorphism other	haplotype associated with sporadic idiopathic dystonia
	216H allele having highly protective effect in patients with the GAG deletion (increased in carriers without dystonia and decreased in carriers with dystonia)

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurology dystonia   specific small molecules that enhance TOR1A activity represent a promising new approach toward therapeutic development for torsion-dystonia, and potentially for other diseases involving the processing of mutant proteins

ANIMAL & CELL MODELS

	ectopic overexpression of both human and C. elegans torsin proteins results in a dramatic reduction of polyglutamine-dependent protein aggregation suggesting a role for torsins in managing protein folding
	It also suggest that breakdown in a neuroprotective mechanism that is, in part, mediated by torsins may be responsible for the neuronal dysfunction associated with dystonia