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FLASH GENE

Symbol

FHL1

contributors: mct/npt/pgu - updated : 04-03-2015

HGNC name	four and a half LIM domains 1
HGNC id	3702

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	SPM1 scapuloperoneal myopathy 1 XMPMA X-linked myopathy with postural muscle atrophy and generalized hypertrophy
Location	Xq26.3      Physical location : 135.228.860 - 135.293.518
Synonym name	four-and-a-half LIM domains 1
	LIM protein SLIMMER
	skeletal muscle LIM-protein 1
	four-and-a-half Lin11, Isl-1 and Mec-3 domains 1
Synonym symbol(s)	SLIM1, FHL1B, KYO-T, KYOT2, bA535K18.1, FLH1A, MGC111107

DNA

TYPE	functioning gene
STRUCTURE	64.56 kb     8 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

text	the first two exons are thought to be noncoding, exons 3 to 8 are alternatively spliced and give rise to three major transcribed isoforms: FHL1A, FHL1B, and FHL1C (PMID: 19716112)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001159700 7 splicing 2455 NP_001153172 31.5 280 . predominantly expressed in skeletal and cardiac striated muscles . expressed in many cell types, with highest levels in skeletal muscle, intermediate levels in the heart and low expression in placenta, ovary, prostate, testis, small intestine, colon and spleen 2012 22523091 also called FHL1A/SLIM1 localizing at focal adhesions 4.5 LIM domains NM_001159702 8 splicing 2724 NP_001153174 - 323 . nuclear . in striated muscles and also in brain . expressed in brain, skeletal muscle and, to a lesser extent, in heart, colon, prostate and small intestine 2012 22523093 FHL1B/SLIM3, slimmer lack exon 4 and contain a C-terminal putative binding domain for J-recombination signal protein (RBP-J) interacts with SIVA1 and delays skeletal myoblast apoptosis (PMID: 19643733) shuttle between nucleus and cytoplasm at different phases of the cell cycle FHL1B/PPP2CA interaction may illustrate a novel cell-cycle regulatory pathway (PMID: 20969868) one of the roles of FHL1B is to act as a specific regulator of PPP2CA in human muscles and brain (PMID: 20969868) contains the LIM domains 1–3 plus nuclear localization and export signals, as well as an RBP-J binding region NM_001159704 6 - 2906 NP_001153176 - 280 - - NM_001159701 6 - 2331 NP_001153173 - 309 - 1999 9929984 NM_001159703 6 - 2337 NP_001153175 - 194 - 1999 9929984 NM_001449 7 - 2524 NP_001440 - 280 - 1999 9929984 NM_001167819 7 splicing 2392 isoform 8 - 280 . specifically expressed in testis, skeletal muscle, and heart at a relatively low level, also seen in aorta, left atrium, left, and right ventricles at low level . expressed at much lower levels in heart, testis and skeletal muscle 2011 22053194 also called isoform FHL1C, or KyoT2 loss of exon 4 contains a single zinc finger and two tandem repeats of LIM domains at the N-terminus followed by a putative RBP-J binding region at the C-terminus homolog of murine Kyot2 localized both in the nucleus and cytoplasm 2.5 LIM domains is a binding partner for KCNA5 FHL1C could induce TJP1 translocating into nucleus, and could contribute to the epithelial-mesenchymal transition (EMT) (PMID: 24657059) NM_001159699 6 - 2460 NP_001153171 - 296 - 1999 9929984

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       predominantly Homo sapiens Adult Digestive liver       moderately   mouth tongue     highly Nervous brain       moderately Reproductive female system placenta     moderately Respiratory lung       moderately Urinary kidney       moderately

tissue

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

cells

System Cell Pubmed Species Stage Rna symbol Muscular myocyte Homo sapiens

cell lineage	myoblasts, myotubes
cell lines
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	four and a half LIM domains (Lin-11, Isl-1, Mec3), which are highly conserved sequences constituted by two zinc fingers in tandem, implicated in numerous interactions
	a novel C terminal 96 AAs with three potential nuclear localization signals (NLS)
	a putative nuclear export sequence and 27AA identical to the RBPJ region of KyoT2

HOMOLOGY

Homologene

FAMILY

CATEGORY

adhesion

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytoskeleton
	intracellular,nucleus,nucleoplasm
text	with isoforms FHL1A, FHL1B,(SLIM1) localizing at focal adhesions and SLIM3 (slimmer) in the nucleus of myoblasts and cytoplasm of myotubes
	can be localized to the sarcolemma, sarcomere, and nucleus of muscle cells
	localized within the cytoskeleton and the nucleus and can shuttle between these compartments
	mainly localize to the sarcomeric I-band, but also to a lesser extent to the M-band of the sarcomere in skeletal myocytes

basic FUNCTION	sugesting distinct roles in the cytoskeleton and in nuclear-cytoplasmic communication
	probably related to neural differentiation
	playing a role in the development and maintenance of muscle tissue, in sarcomere synthesis and assembly
	regulator of myosin-binding protein C activity and playinga role in sarcomere assembly
	LIM domain protein that suppresses the RBPJ-mediated transcriptional activation
	might inhibit the RBPJ-mediated transactivation through intracellular domain of Notch by recruiting co-suppressors such as CBX4
	implicated in sarcomere assembly by interacting with myosin binding protein-C
	suggested to contribute to sarcomere synthesis, assembly and biomechanical stress sensing
	cooperative regulation of VEGFA signaling by FHL1 and SMAD4 was evidenced, which may provide a novel regulation mechanism underlying cancer development and progression
	FHL1 and FHL2 are novel cardiac PRKD1 partners, which differentially facilitate PRKD1 activation and HDAC5 phosphorylation by distinct neurohormonal stimuli, but are unlikely to regulate MEF2A-driven transcriptional reprogramming
	can be an acting molecule mediating both signaling pathways during osteogenesis

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

FHL1 exists as part of a complex that binds with PDLIM1, GSN and ACTN1

INTERACTION

DNA

RNA

small molecule

protein	interacting with AKAP1 and FRAP1 for regulating ribosomal protein genes
	interacting with myosin-binding protein C (MYBPC), and may contribute to muscle cytoarchitecture by interacting
	interacting with CBX4
	talin1 is a new interacting partner of FHL1
	FHL1, FHL2, and FHL3 physically and functionally interact with SMAD2, SMAD3, and SMAD4, important regulators of cancer development and progression, in a TGF-beta-independent manner
	interaction between ubiquitin-specific protease 15 (USP15) and skeletal muscle LIM protein 1 (FHL1)
	binds to the EP300/CREBBP co-activators and disrupts binding with HIF1A
	FHL1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics
	NFATC1-mediated transcription regulates UTRN expression and FHL1 which promotes muscle hypertrophy, is a transcriptional activator of NFATC1
	binds RBPJ with high affinity and competes with coactivators, such as NOTCH1, for binding RBPJ

cell & other

REGULATION

Other	regulated by TLX1
	regulation is hypoxia-inducible transcription factor dependent

ASSOCIATED DISORDERS

corresponding disease(s)

XMPMA , SPM1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   particularly in the pulmonary vasculature, in lungs from patients with idiopathic pulmonary arterial hypertension constitutional     --low   in hypertrophic cardiomyopathy and failing hearts constitutional     --over   in hypertrophic cardiomyopathy (HCM) constitutional     --over   in smooth muscle in Hirschsprung disease (HSCR) might be associated with intestinal wall remodeling in HSCR and might be one of the risk factors for gastrointestinal motor dysfunction

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neuromuscular myopathy   FHL1-NFATC1-UTRN signaling axis that can functionally compensate for dystrophin and treat DMD

ANIMAL & CELL MODELS

W122S mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle, and loss of function is responsible for the late-onset mild myopathy in the Fhl1 W122S knock-in mice