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FLASH GENE

Symbol

ACTN3

contributors: mct - updated : 24-03-2021

HGNC name	actinin, alpha 3
HGNC id	165

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	16.94 kb     21 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001104 21 - 2858 103.3 901 - 2020 32866209 NM_001258371 21 - 3092 NP_001245300 - 944 - 2020 32866209

EXPRESSION

Type	restricted

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

tissue

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

cells

System Cell Pubmed Species Stage Rna symbol Skeleton osteoblast Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	one actin-binding domain
	two ch (calponin-homology) domains
	two ef-hand calcium-binding domains
	four spectrin repeats

mono polymer

homomer , dimer

HOMOLOGY

interspecies

ortholog to rattus Actn3

Homologene

FAMILY

CATEGORY

motor/contractile

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
text	localized to the Z-disc and analogous dense bodies, where it helps to anchor the myofibrillar actin filaments

basic FUNCTION	one of many genes contributing to genetic variation in muscle performance and adaptation to exercise
	potentially participating with ACTN2 in sequestering parafibromin (HRPT2) in the cytoplasmic compartment
	potentially regulates PYGM activity by altering its level of phosphorylation
	presence of ACTN3 protein is associated with improved sprint/power performance in athletes and the general population
	major component of the Z-disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array
	potentially necessary for optimal forceful repetitive muscle contractions
	is an integral part of the Z line of the sarcomere
	role of ACTN3 in contractile properties of human single muscle fibers
	play a role in the regulation of calcineurin signaling
	ACTN3 influences likely sarcomeric composition in a dose-dependent fashion in skeletal muscle, which translates directly to function
	role in modulating muscle metabolism with altered fatiguability
	play a role in regulating fiber size and muscle growth during embryonic muscle development
	stabilizes the contractile apparatus at the Z-line in skeletal muscle cell fast fibers

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule	metal binding,
	Ca2+

protein

among UPR-related transcription factors, XBP1, ATF4 and ATF6 downregulated ACTN3 promoter activity

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

ACTN3D

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional         changes the overall protein composition of fast fiber Z-disks and alters their elastic properties, providing a mechanistic explanation for the loss of force generation and increased susceptibility to eccentric damage in ACTN3-deficient individuals constitutional       loss of function reduces the activity of glycogen phosphorylase and results in a fundamental shift toward more oxidative pathways of energy utilization constitutional       loss of function is underrepresented in elite sprint/power athletes and has been associated with reduced muscle mass and strength in humans constitutional       loss of function is accompanied by a shift toward a slower skeletal muscle phenotype, and deficient humans exhibit improved cold tolerance during cold-water immersion constitutional         changes in Ca2+ handling in the absence of ACTN3 are consistent with cold acclimatisation and thermogenesis, and offer an additional explanation for the positive selection of the ACTN3 577X null allele in populations living in cold environments during recent evolution tumoral     --over   adversely affected the survival of AML patients

Susceptibility

to passive muscle stiffness

Variant & Polymorphism other	R577X associated to elite athlete status (overrepresentation of the 577XX genotype among elite endurance athletes)
	R577X polymorphism of the ACTN3 has been associated
	with passive muscle stiffness
	ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients
	ACTN3 R577X polymorphism could be a novel target for readthrough therapy, which may affect athletic and muscle performance

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	Actn3 KO mice showing reductions in muscle strength, increased endurance capacity, reduced fast fiber size, shifts in fast fiber metabolism toward oxidative metabolism
	Actn3(-/-) mouse displays significantly reduced bone mass, with reduced cortical bone volume (-14p100) and trabecular number (-61p100) seen by microCT
	deficiency in the Actn3 KO mouse results in a shift in fast-twitch fibres towards oxidative metabolism, which would be more "energy efficient" in famine, and beneficial to endurance performance
	Actn3 KO mice were significantly lighter than their WT counterparts and therefore showed an improved cold tolerance after normalizing for body weight