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FLASH GENE

Symbol

KL

contributors: mct - updated : 14-09-2018

HGNC name	klotho
HGNC id	6344

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

text	ADAM10 and ADAM17, can cleave the extracellular domain of KL to generate 116- and 63-kDa KL fragments

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004795 5 splicing 5012 NP_004786 116.2 1012 in serum and cerebrospinal fluid (CSF) 2016 27543985 isoform a, membrane-bound isoform (type I transmembrane protein) long isoform I65 - - - 65 - - 2016 27543985 65 KDa soluble KL exerting an anti-fibrotic effect in cardiac myofibroblasts

EXPRESSION

Type

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 vessel aorta     highly Homo sapiens Endocrine parathyroid         Homo sapiens Nervous plexus choroid         Homo sapiens Urinary kidney tubule convoluted tubule distal tubule highly Homo sapiens   kidney         Homo sapiens   kidney tubule convoluted tubule proximal tubule   Homo sapiens Visual eye retina       Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

pregnancy

Text

placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	an N terminal signal sequence
	an extracellular domains with two internal repeats, each repeat sharing 20–40 p100 sequence identity to mammalian lactase glycosylceramidase, beta-glucosidase-like domain
	a short intracellular domain
	second hydrolase domain of Klotho interacts with sixth and seventh Ig domains of KDR and the third extracellular loop of TRPC1 (
	C-terminal region is critical for Klotho specificity determination and interaction

conjugated

GlycoP

isoforms

Precursor

HOMOLOGY

interspecies	homolog to murine Kl (86.2pc)
	homolog to rattus Kl (84.8pc)

Homologene

FAMILY	glycosyl hydrolase 1 family
	Klotho subfamily

CATEGORY

enzyme , secretory

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
text	type1 membrane protein
	ADAM10 and ADAM17 are capable of shedding KL from the plasma membrane, and that insulin can stimulate KL shedding

basic FUNCTION	beta-glucosidase activity
	may be involved in genetic regulation of common age-related diseases like osteoporosis and spondylosis
	playing a crucial role in the regulation of renal stanniocalcin gene expression at least partly, through the control of circulating calcium and phosphate concentrations
	activating a cell surface channel by hydrolysis of its extracellular N-linked oligosaccharides, as TRPV5
	soluble isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling
	regulating cellular senescence by repressing the p53/p21 pathway
	fundamental roles in the regulation of calcium metabolism
	involved in the inhibition of the insulin signaling pathway
	functions as an aging-suppressor gene that extends life span when overexpressed and accelerates aging-like phenotypes when disrupted in mice
	single-pass transmembrane protein that binds to multiple fibroblast growth factor (FGF) receptors and functions as a co-receptor for FGF23, a bone-derived hormone
	can regulate multiple growth factor signaling pathways, including insulin/IGF1 and Wnt, and the activity of multiple ion channels
	works as a hormonal factor to promote adipocyte differentiation in the early days, during the period of transient proliferation in the differentiation process, and may play an essential role in adipocyte differentiation
	can be shed and act as a circulating hormone and is a putative tumor suppressor in breast cancer
	key regulator of mineral homeostasis
	associated with KDR/TRPC1 in causing cointernalization, and thus regulating TRPC1–mediated Ca2+ entry to maintain endothelial integrity
	likely to be a kidney-derived vasoprotective protein
	regulating KDR/TRPC1–mediated Ca2+ influx to maintain endothelial biological homeostasis
	functions as an anti-ageing factor through the suppression of DDX58-mediated inflammation
	renal KL controls mineral metabolism by directly modulating tubular reabsorption of phosphate and calcium and by acting as a co-receptor for the phosphaturic and vitamin D-regulating hormone FGF23
	modulates the stress response in human senescent endothelial cells
	has an important role in regulating ER stress and loss of KL is causally linked to ER stress-induced apoptosis
	is a novel player in the retina, with a clear connection to photoreceptor cell death as well as with an influence on retinal organization
	is an important regulator of retinal pigment epithelium (RPE) homeostasis
	role for the antiaging hormone KL in the regulation of prenatal and postnatal hematopoiesis
	functions as the obligatory co-receptor for fibroblast growth factor-23 (FGF23), a bone-derived phosphaturic hormone
	KL expression may be modulated by skeletal muscle activity
	circulating alpha-Klotho protects the lung against oxidative damage and apoptosis partly via increasing endogenous antioxidative capacity in pulmonary epithelia
	KL functions include inhibition of local phosphate transport in vascular cells, phenotypic switches of vascular cellular elements into bone-forming cells, attenuation of matrix mineralization and calcification, and also preservation of endothelial functional properties and viability
	is an important molecule in aging processes and its overexpression results in longevity
	is an antiaging gene encoding a single-pass transmembrane protein, KL, which serves as an aging suppressor through a wide variety of mechanisms, such as antioxidation, antisenescence, antiautophagy
	exerts its renal protection by targeted inhibition of renin-angiotensin system (RAS), a pathogenic pathway known to play a key role in the evolution and progression of hypertension and chronic kidney disorders
	up-regulates the excitatory glutamate transporters SLC1A3 and SLC1A2 and thus participates in the regulation of neuronal excitation
	is implicated in the process of angiogenesis of human dermal microvasculature
	soluble KL plays a stimulatory role in cardiac myofibroblast growth and activity through FGF pathway
	in proximal renal tubules, FGF23 suppresses phosphate reabsorption by a KL dependent activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and of serum/glucocorticoid-regulated kinase-1 (SGK1)

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

carbohydrate

signaling

signal transduction

renal FGF23-KL signaling, which is disrupted in chronic kidney disease, is essential for homeostatic control of mineral metabolism

a component

INTERACTION

DNA

RNA

small molecule

protein	vitamin D binding
	can directly interact with FGF receptors as well as with FGF19 and FGF23
	binds directly to KDR and TRPC1 and strengthens the association to promote their cointernalization (
	interacts with DDX58 and this interaction inhibits DDX58-induced expression of IL6 and IL8
	FGF23 binding to FGFR3 was enhanced in the presence of KL
	is a novel, powerful regulator of the excitatory amino acid transporters SLC1A1, SLC1A6
	KL and sialidase regulate TRPV5 membrane stabilization in a different manner
	Klotho upregulates KCNQ1/KCNE1 channel activity by “mainly” enhancing channel protein abundance in the plasma cell membrane
	KL expression was associated with expression of the non-sulfated B3GAT1 epitope
	regulates diverse calcium and potassium ion channels, as well as several carriers including the Na(+)-coupled excitatory amino acid transporters (SLC1A1, SLC1A6, SLC34A1, SLC34A2)
	Klotho protein up-regulates the activity of creatine transporter SLC6A8 by stabilizing the carrier protein in the cell membrane, an effect requiring beta-glucuronidase activity of KL protein
	CDKN2A plays a previously unrecognized role in downregulating KL expression during ageing
	MTOR signaling inhibition ameliorates vascular calcification via KL upregulation
	DGKE regulated KL expression, at least partly via the transcription factor Krüppel-like factor (KLF15)

cell & other

REGULATION

induced by

statin

inhibited by

angiotensin II through the regulation of Ras homolog gene family, member A

Other

regulated by insulin (stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17)

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   down-regulated in renal cell carcinomas, hepatocellular carcinomas constitutional     --low   down-regulated in chronic renal failure kidney, and decrease in circulating Klotho may contribute to vascular lesions in the patients with chronic renal failure ( constitutional       loss of function downregulates SIRT1 activity in arterial endothelial and smooth muscle cells constitutional     --over   in patients with diabetes and s-KL levels, but decreased with increasing albumin excretion

Susceptibility

to early-onset coronary artery disease and atherosclerosis to osteoporosis in postmenopausal women to decreased longevity to variation of BMD in male adults to breast and ovarian cancers

Variant & Polymorphism SNP , other	associated with decreased longevity
	G395A or C1818T increasing the risk of osteoporosis in postmenopausal women
	allelic variants of Klotho constitute one of the genetic factors influencing BMD in male adults
	KL-VS allele defined by the presence of 6 SNPs in exon 2 and flanking sequence impairs the trafficking and catalytic activity of KL
	some SNPs are associated with sickle cell osteonecrosis
	G395A is associated with blood pressure and C1818T is associated with glucose metabolism in Korean women
	KLOTHO-V allele was associated with increased breast and ovarian cancers risk

Candidate gene	DNA methylation markers of Gastric cancer (GC), which may serve as useful markers that may identify a distinct subset of GC
Marker	reduced serum KL concentrations and decreased vascular KL gene expression were associated with the presence and severity of coronary artery disease (CAD) independently of established cardiovascular risk factors
Therapy target
	System Type Disorder Pubmed cardiovascular aquired   might be a therapeutic target for preventing cardiovascular disease that complicates various diseases such as chronic kidney disease

ANIMAL & CELL MODELS

	transgenic mice
	in klotho-null mice, the activity of calpain is elevated and the activity of its endogenous inhibitor is significantly decreased
	klotho mice have a barely detectable amount of white adipose tissue, increased glucose tolerance and insulin sensitivity
	overexpression of klotho in mice extends life span
	mice heterozygously deficient for klotho gene showed blood flow recovery and impaired angiogenesis after ischemic hindlimb injury
	Klotho-hypomorphic (Klotho(hm)) mice suffer from renal salt wasting and hypovolemia despite hyperaldosteronism
	disruption of the Klotho gene in mice results in hypervitaminosis D and a syndrome resembling accelerated aging that includes osteopenia and vascular calcifications
	in the mdx mouse model of DMD epigenetic silencing of Klotho during muscular dystrophy contributes substantially to lost regenerative capacity and increased fibrosis of dystrophic muscle during late progressive stages of the disease