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FLASH GENE
Symbol KL contributors: mct - updated : 20-04-2010
HGNC name klotho
HGNC id 6344
Location 13q13.1      Physical location : 33.590.570 - 33.640.281
Synonym name
  • murine klotho gene homolog
  • alpha klotho
    • Synonym symbol(s) Klotho, alpha-klotho
    EC.number 3.2.1.31
    DNA
    TYPE functioning gene
    STRUCTURE 49.71 kb     5 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    UBCH7N2 13q12.3 ubiquitin-conjugating enzyme-like HMGB1 13q12 high-mobility group box 1 LOC390392 13 similar to Protein-tyrosine phosphatase, non-receptor type 2 (T-cell protein-tyrosine phosphatase) (TCPTP) D13S106E 13q12-q14 highly charged protein ALOX5AP 13q12 arachidonate 5-lipoxygenase-activating protein LOC387917 13 LOC387917 FLJ14834 13q12.3 hypothetical protein FLJ14834 MGC40178 13q12.3 hypothetical protein MGC40178 HSPH1 13q12.3 heat shock 105kDa/110kDa protein 1 B3GTL 13q12.3 beta 3-glycosyltransferase-like GREAT 13q12.3 beta 3-glycosyltransferase-like LOC196549 13q12.3 similar to hypothetical protein FLJ20897 13CDNA73 13q12.3 hypothetical protein CG003 BRCA2 13q12.3 breast cancer 2, early onset IFIT1P 13q12-q13 interferon-induced protein with tetratricopeptide repeats 1, pseudogene CG018 13q12-q13 hypothetical gene CG018 PRO0297 13q12-q13 hypothetical gene CG018 LOC88523 13q12.3 CG016 CG005 APRIN 13q12.3 androgen-induced proliferation inhibitor LOC122038 13q13.1 similar to Mitochondrial import receptor subunit TOM22 homolog (Translocase of outer membrane 22 kDa subunit homolog) (hTom22) (1C9-2) KL 13q12 klotho LOC387918 13 LOC387918 STARD13 13q12-q13 START domain containing 13 RFC3 13q12.3-q13 replication factor C (activator 1) 3, 38kDa NBEA 13q13 neurobeachin MAB21L1 13q13.1-q13.2 mab-21-like 1 (C. elegans)
    RNA
    TRANSCRIPTS type messenger
    text ADAM10 and ADAM17, can cleave the extracellular domain of KL to generate 116- and 63-kDa KL fragments
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    5 splicing 5012 116.2 1012 in serum and cerebrospinal fluid (CSF) 2007 18056631
  • isoform a, membrane-bound isoform (typeI transmembrane protein)
  • long isoform
    		•
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularvesselaorta  highly Homo sapiens
    Urinarykidneytubuleconvoluted tubule highly 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
    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
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism carbohydrate
    signaling signal transduction
    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
    • 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)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein 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 (
    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
    Therapy target
    SystemTypeDisorderPubmed
    cardiovascularaquired 
    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