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FLASH GENE

Symbol

RYR1

contributors: mct - updated : 31-08-2018

HGNC name	ryanodine receptor 1 (skeletal)
HGNC id	10483

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CCO central core disease of muscle MHS1 malignant hyperthermia susceptibility, 1 MMDO multiminicore disease with external ophthalmoplegia
Location	19q13.2      Physical location : 38.924.339 - 39.078.203
Synonym name	sarcoplasmic reticulum calcium release channel
	skeletal muscle ryanodine receptor
	type 1-like ryanodine receptor
	sarcoplasmic reticulum calcium release channel
Synonym symbol(s)	HRR, RYR, MHS, RYDR, SKRR

DNA

TYPE	functioning gene
STRUCTURE	153.87 kb     106 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter (TATA box)
	Binding site   transcription factor
text structure	five TATA boxes, several transcription activator sites

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	cen - D19S49 - D19S75 - D19S191 - RYR1 ,D19S378 - D19S18 /D19S190 - D19S47 - qter
Text	see CCO

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000540 106 - 15391 NP_000531 565 5038 - 2007 17707769 isoform 1 NM_001042723 105 - 15376 NP_001036188 564 5033 - 2007 17707769 lacking an alternate in-frame exon, compared to variant 1 isoform 2 is shorter than isoform 1

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 Cardiovascular heart         Digestive pharynx       highly Nervous brain         Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal   highly

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune dendritic cell Lymphoid/Immune T cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

IMPRINTING

maternally

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminal domain D3 involved in calcium dependent regulation of the calcium release channel
	N-terminal and central domain elements are closely apposed near the FKBP binding site
	five MIR and RIH domain
	a central domain of RYR1 is the transducer for long-range allosteric gating of channel opening
	three SPRY domain, and ASI/basic
	SPRY2 domain interact in an F loop regulatory module , and SPRY2 domain forms a link between the N-terminal gating ring and the clamp region

mono polymer

homomer , tetramer

HOMOLOGY

interspecies

homolog to murine Ryr1 (96.00pc)

Homologene

FAMILY

ryanodine receptor family

CATEGORY

motor/contractile , receptor membrane

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,endoplasmic reticulum

basic FUNCTION	involved in contraction of skeletal muscle triggered by release of calcium ions from sarcoplasmic reticulum following depolarization of transverse tubules
	with SEPN1, are both required for normal muscle development and differentiation and for some calcium mobilization events in the embryo
	with SERCA2B (ATP2A2 variant B) is involved in vasodilatation in pulmonary arterial smooth muscle
	leaky RYR1 contributes to age-related loss of muscle function
	large, homotetrameric sarcoplasmic reticulum membrane protein that is essential for Ca(2+) cycling in both skeletal and cardiac muscle
	RYR1, RYR2, RYR3 strongly regulate Ca2+ influx in human T cells
	RYR1, RYR2, RYR3 are important regulators of Ca2+ signaling and Ca2+-dependent functions in human immune cells, which could be potentially used as a tool for modulating immune responses
	stabilization of RYR1 might be effective not only in neuronal death but also in neuronal dysfunction of Huntington disease
	RYR1 release Ca(2+) from the sarcoplasmic reticulum to initiate skeletal muscle contraction
	role for RYR1 on both the pre- and postsynaptic sides of the neuromuscular junction (NMJ)
	important non-contractile role of RYR1 or RYR1-mediated Ca(2+) signaling during muscle organ development
	intracellular calcium channel responsible for rapid release of Ca(2+) from the sarcoplasmic/endoplasmic reticulum (SR/ER) to the cytoplasm, which is essential for the excitation-contraction (E-C) coupling of cardiac and skeletal muscles
	plays a crucial role in vasoconstriction and hemostasis

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

cellular trafficking transport

text	cellular calcium ion homeostasis

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	binding SEPN1 (RyR channel is a “redox sensor” regulated by a number of associated proteins including SEPN1)
	interacting with TRPC3 (TRPC3 and RYR1 are functionally engaged via linker proteins in skeletal muscle)
	CLIC2 can interact with RYR1 and modulate its channel activity
	CHERP is an RYR1 interacting protein that may be involved in the regulation of excitation-contraction coupling
	S100A1 and calmodulin bind to an overlapping domain on the RYR1 to tune the Ca2+ release process, and thereby regulate skeletal muscle function
	interaction between FKBP1A and RYR1, RYR3 and ITPR1
	RYR1, RYR2, RYR3 regulate SOCE by controlling Ca2+ store refilling
	because SOCE regulates a variety of Ca2+-dependent T cell responses, RYR1, RYR2, RYR3 are in a position to control vital T cell functions
	CAV3 forms a disc-shaped nonamer that binds the Ca(2+)-release channel, RYR1
	FKBP1A promotes the RYR1 closed state, thereby inhibiting Ca2+ leakage in resting muscle
	C-terminal domain of ASPH binds to residues including the S1-S2 linker of RYR1 and N-terminal domain of ASPH binds between RYR1 residues 1078 and 2156
	CALM1 and S100A1 can concurrently bind to and functionally modulate RYR1 and RYR2, but this does not involve direct competition at the RYR CALM binding site
	SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RYR1), and its deficiency results in myospryn complex abnormalities

cell & other

REGULATION

Other

triggered by the dehydropyridine receptor(s)

ASSOCIATED DISORDERS

corresponding disease(s)

CCO , MHS1 , MMDO

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       loss of function altered RYR1 function may contribute to the neurodegeneration in Huntington disease constitutional germinal mutation       associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome

Susceptibility

to aneurysmatic subarachnoid hemorrhage

Variant & Polymorphism other	rare RYR1 variants in patients suffering from aneurysmatic subarachnoid hemorrhage

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neuromuscular     RyR activity may not be irreversibly damaged in patients with SEPN1-associated disease and might provide a target for therapeutic intervention neurology     altered RYR function is involved in neuronal cell death, and its stabilization might be beneficial for treatment of Huntington disease (dantrolene or other similar RYR inhibitors may be beneficial for HD patients)

ANIMAL & CELL MODELS