KL (klotho)

Gene

• Entrez ID: 9365
• Gene name: Klotho
• Gene symbol: KL
• Synonyms: HFTC3, KLA
• Chromosome: 13
• Chromosome location: 13q13.1
• Summary: This gene encodes a type-I membrane protein that is related to beta-glucosidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing and bone loss. [provided by RefSeq, Jul 2008]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs121908423	A>G	Likely-pathogenic, pathogenic	Intron variant, missense variant, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT019099	hsa-miR-335-5p	Microarray	18185580
MIRT053233	hsa-miR-199a-5p	EMSA, FACS, Flow, GFP reporter assay, Gluc reporter assay, GUS reporter assay, HITS-CLIP, Immunoblot, Immunocytochemistry, Immunofluorescence, Immunohistochemistry, Luciferase reporter assay, qRT-PCR, Western blot, In situ hybridization	24655788
MIRT445349	hsa-miR-3163	PAR-CLIP	22100165
MIRT733670	hsa-miR-10b-5p	Luciferase reporter assay, Western blot	25988292

Transcription factors

Transcription factor	Regulation	Reference
HMGA1	Activation	15378028

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000165	Process	MAPK cascade	TAS
GO:0004566	Function	Beta-glucuronidase activity	IEA
GO:0005104	Function	Fibroblast growth factor receptor binding	IBA	21873635
GO:0005179	Function	Hormone activity	IEA
GO:0005499	Function	Vitamin D binding	IEA
GO:0005576	Component	Extracellular region	TAS
GO:0005783	Component	Endoplasmic reticulum	IBA	21873635
GO:0005886	Component	Plasma membrane	TAS
GO:0005887	Component	Integral component of plasma membrane	TAS	9464267
GO:0005975	Process	Carbohydrate metabolic process	IEA
GO:0006112	Process	Energy reserve metabolic process	IEA
GO:0007568	Process	Aging	IMP	11792841
GO:0008286	Process	Insulin receptor signaling pathway	IEA
GO:0008422	Function	Beta-glucosidase activity	IBA	21873635
GO:0008543	Process	Fibroblast growth factor receptor signaling pathway	IBA	21873635
GO:0008543	Process	Fibroblast growth factor receptor signaling pathway	TAS
GO:0016324	Component	Apical plasma membrane	IEA
GO:0017134	Function	Fibroblast growth factor binding	IBA	21873635
GO:0017134	Function	Fibroblast growth factor binding	IPI	18829467
GO:0030501	Process	Positive regulation of bone mineralization	IMP	12110410
GO:0051897	Process	Positive regulation of protein kinase B signaling	TAS
GO:0055074	Process	Calcium ion homeostasis	IEA
GO:0070062	Component	Extracellular exosome	HDA	19056867, 23533145
GO:0090080	Process	Positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	IEA

Other IDs

• MIM: 604824
• HGNC: 6344
• e!Ensembl: ENSG00000133116

Protein

• UniProt ID: Q9UEF7
• Protein name: Klotho (EC 3.2.1.31) [Cleaved into: Klotho peptide]
• Protein function: May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 239 and 872, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D (By similarity). Essential factor for the specific interaction between FGF23 and FGFR1 (By similarity). ; The Klotho peptide generated by cleavage of the membrane-bound isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling.
• PDB: 5W21
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00232	Glyco_hydro_1	57 → 381	Glycosyl hydrolase family 1	Domain
  PF00232	Glyco_hydro_1	378 → 506	Glycosyl hydrolase family 1	Domain
  PF00232	Glyco_hydro_1	515 → 953	Glycosyl hydrolase family 1	Domain

• Sequence:

  MPASAPPRRPRPPPPSLSLLLVLLGLGGRRLRAEPGDGAQTWARFSRPPAPEAAGLFQGT
  FPDGFLWAVGSAAYQTEGGWQQHGKGASIWDTFTHHPLAPPGDSRNASLPLGAPSPLQPA
  TGDVASDSYNNVFRDTEALRELGVTHYRFSISWARVLPNGSAGVPNREGLRYYRRLLERL
  RELGVQPVVTLYHWDLPQRLQDAYGGWANRALADHFRDYAELCFRHFGGQVKYWITIDNP
  YVVAWHGYATGRLAPGIRGSPRLGYLVAHNLLLAHAKVWHLYNTSFRPTQGGQVSIALSS
  HWINPRRMTDHSIKECQKSLDFVLGWFAKPVFIDGDYPESMKNNLSSILPDFTESEKKFI
  KGTADFFALCFGPTLSFQLLDPHMKFRQLESPNLRQLLSWIDLEFNHPQIFIVENGWFVS
  GTTKRDDAKYMYYLKKFIMETLKAIKLDGVDVIGYTAWSLMDGFEWHRGYSIRRGLFYVD
  FLSQDKMLLPKSSALFYQKLIEKNGFPPLPENQPLEGTFPCDFAWGVVDNYIQVDTTLSQ
  FTDLNVYLWDVHHSKRLIKVDGVVTKKRKSYCVDFAAIQPQIALLQEMHVTHFRFSLDWA
  LILPLGNQSQVNHTILQYYRCMASELVRVNITPVVALWQPMAPNQGLPRLLARQGAWENP
  YTALAFAEYARLCFQELGHHVKLWITMNEPYTRNMTYSAGHNLLKAHALAWHVYNEKFRH
  AQNGKISIALQADWIEPACPFSQKDKEVAERVLEFDIGWLAEPIFGSGDYPWVMRDWLNQ
  RNNFLLPYFTEDEKKLIQGTFDFLALSHYTTILVDSEKEDPIKYNDYLEVQEMTDITWLN
  SPSQVAVVPWGLRKVLNWLKFKYGDLPMYIISNGIDDGLHAEDDQLRVYYMQNYINEALK
  AHILDGINLCGYFAYSFNDRTAPRFGLYRYAADQFEPKASMKHYRKIIDSNGFPGPETLE
  RFCPEEFTVCTECSFFHTRKSLLAFIAFLFFASIISLSLIFYYSKKGRRSYK

• Sequence length: 1012

Pathways

KEGG:

Pentose and glucuronate interconversions
Ascorbate and aldarate metabolism
Metabolic pathways
Longevity regulating pathway
Parathyroid hormone synthesis, secretion and action
Endocrine and other factor-regulated calcium reabsorption

Reactome:

PI3K Cascade
PIP3 activates AKT signaling
FGFR1c and Klotho ligand binding and activation
Constitutive Signaling by Aberrant PI3K in Cancer
Phospholipase C-mediated cascade: FGFR1
Downstream signaling of activated FGFR1
SHC-mediated cascade:FGFR1
PI-3K cascade:FGFR1
FRS-mediated FGFR1 signaling
Negative regulation of FGFR1 signaling
RAF/MAP kinase cascade
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

Associated diseases

Causal
Disease name	Disease term	dbSNP ID	References
Diabetes mellitus	Diabetes Mellitus, Non-Insulin-Dependent	rs587776515, rs61730328, rs606231121, rs606231122, rs79020217, rs77625743, rs78378398, rs606231123, rs4402960, rs1362648752, rs3745368, rs3792267, rs3842570, rs5030952, rs2975760, rs119489103, rs7903146, rs12255372, rs11196205, rs104893649, rs80356624, rs80356616, rs80356625, rs80356611, rs104894237, rs80356613, rs137852740, rs137852786, rs387906407, rs151344623, rs28938469, rs28936371, rs137852672, rs80356637, rs80356642, rs80356653, rs137852673, rs137852674, rs80356634, rs80356651, rs193929360, rs137853334, rs137853335, rs137853336, rs-1, rs1600731198, rs137853338, rs121964882, rs121964883, rs387906511, rs121964884, rs121964885, rs2147483647, rs387906512, rs121964887, rs121964888, rs121964889, rs121964890, rs121964891, rs28934878, rs74315383, rs121964893, rs886037620, rs886037621, rs80356663, rs121434593, rs121913150, rs587776825, rs137853236, rs2135842335, rs137853237, rs137853238, rs2135818776, rs1566092470, rs1463923467, rs137853243, rs137853244, rs2135839114, rs137853245, rs2135847417, rs121918407, rs104894005, rs104894006, rs80356655, rs104894008, rs104894009, rs104894010, rs104894011, rs80356654, rs104894016, rs193929376, rs193929374, rs193929375, rs193929373, rs80356666, rs80356669, rs80356664, rs193929366, rs1048095, rs193929355, rs193929356, rs1259467443, rs104893642, rs387906777, rs387906779, rs141804752, rs182349376, rs184917682, rs193922396, rs193922400, rs193922401, rs137852676, rs193922407, rs193922638, rs193922257, rs193922258, rs193922259, rs193922260, rs193922261, rs193922262, rs193922263, rs193922264, rs193922265, rs193922268, rs193921338, rs193922269, rs193922272, rs193922273, rs193922275, rs193922278, rs193922279, rs193922280, rs193922281, rs193922282, rs193922283, rs193922284, rs193922286, rs193922287, rs193922289, rs193922291, rs193922295, rs193922297, rs193922300, rs193922302, rs193922303, rs193922308, rs193922313, rs193922314, rs144723656, rs193922315, rs193922316, rs193922317, rs148311934, rs193922319, rs193922320, rs193922326, rs193922329, rs193922330, rs193922331, rs193922335, rs193922336, rs193922338, rs193922340, rs193922341, rs193922471, rs193922475, rs193922476, rs193922479, rs193922355, rs193922356, rs193922576, rs193922578, rs193922582, rs193922588, rs193922592, rs193922594, rs193922596, rs386134267, rs193922598, rs193922599, rs193922600, rs193922604, rs193922605, rs397514580, rs397515519, rs267601516, rs587780343, rs587780345, rs587780346, rs587780347, rs587780357, rs148954387, rs61736969, rs587783673, rs587783672, rs587783669, rs786204676, rs794727236, rs151344624, rs794727775, rs794727839, rs199946797, rs869320673, rs796065047, rs759072800, rs797045595, rs797045209, rs797045207, rs797045213, rs797045623, rs863225280, rs149703259, rs864321656, rs139964066, rs777870079, rs878853246, rs769268803, rs886039380, rs886041392, rs886041391, rs886042610, rs143064649, rs1057516192, rs746480424, rs1057516281, rs576684889, rs754728827, rs1057520291, rs1057520779, rs893256143, rs1057520504, rs1057524790, rs1057524902, rs1057524904, rs1057524905, rs764232985, rs1064793998, rs1064794268, rs769086289, rs369429452, rs1085307913, rs1131691416, rs765432081, rs1131692182, rs748749585, rs1554335441, rs762263694, rs1312678560, rs767565869, rs1375656631, rs1554335391, rs1360415315, rs1554335616, rs1554335752, rs1554909277, rs769518471, rs757171524, rs768951263, rs762703502, rs1555212248, rs1555212359, rs1555813319, rs1555816654, rs371977235, rs76474829, rs200998587, rs1415041911, rs1554334894, rs1260178539, rs1554335421, rs1555211904, rs779184183, rs1554335564, rs200670692, rs1400535021, rs1554334872, rs1555212749, rs1553876668, rs1553878211, rs954727530, rs1554924035, rs372307320, rs925231098, rs1554913069, rs1554933565, rs766431403, rs746714109, rs751279984, rs770664202, rs1008906426, rs758844607, rs1554924540, rs1566092307, rs753998395, rs1565885935, rs1167124132, rs1376796469, rs556436603, rs1562715657, rs1486280029, rs1564869850, rs755259997, rs769569410, rs1172328722, rs1286294151, rs1375557127, rs1568731279, rs1562715426, rs556581174, rs1564865302, rs1565886545, rs776793516, rs1568724014, rs1392795567, rs781260712, rs1562719705, rs1382448285, rs1564977373, rs750586210, rs1598842892, rs1583592247, rs780612692, rs1593060859, rs1476637197, rs751279776, rs1593060890, rs1191912908, rs1167675604, rs1583601110, rs1593058932, rs778611627, rs753296261	28869590
Colorectal cancer	Colorectal Carcinoma	rs137854568, rs137854573, rs137854575, rs387906234, rs1801155, rs121908380, rs121908702, rs267606674, rs-1, rs4939827, rs794729661, rs121909055, rs281865417, rs267606884, rs28934575, rs587776769, rs104893815, rs587776800, rs63750198, rs63751109, rs863223312, rs63750710, rs63751615, rs63750206, rs63750781, rs63750899, rs63750691, rs63750217, rs121912965, rs63749939, rs63751194, rs63750693, rs63750540, rs63751221, rs193922370, rs80359596, rs397514632, rs483352909, rs200495564, rs397514684, rs397516436, rs398122386, rs79512956, rs74953290, rs587779001, rs63750677, rs63749837, rs267607816, rs63751715, rs267607819, rs267607815, rs267607822, rs63749906, rs587778883, rs63750472, rs63751012, rs63750715, rs63750580, rs267607706, rs267607709, rs267607710, rs587778894, rs63750749, rs63750483, rs63751015, rs63751153, rs63751094, rs63751118, rs63750316, rs63749981, rs587778906, rs267607821, rs587778908, rs63750020, rs587778909, rs63750713, rs267607825, rs63751592, rs281864936, rs587778913, rs587778914, rs63749795, rs63750855, rs63749916, rs63749923, rs63751472, rs63751689, rs267607832, rs267607837, rs267607836, rs587778923, rs63750028, rs587778928, rs587778929, rs587778930, rs63751277, rs587778933, rs267607842, rs267607843, rs63750192, rs587778934, rs63750193, rs587778937, rs587778938, rs267607845, rs63751244, rs63751393, rs63751460, rs267607849, rs267607853, rs267607856, rs267607850, rs63751657, rs267607854, rs267607852, rs587778942, rs63750309, rs63750587, rs63749863, rs63751486, rs63750016, rs63749868, rs63750375, rs63750035, rs63750604, rs63750386, rs63750150, rs63750486, rs63751428, rs267607866, rs63749986, rs63751594, rs63750152, rs63750850, rs267607867, rs267607868, rs63751632, rs267607871, rs63751892, rs587778956, rs63750469, rs587778958, rs63749792, rs267607875, rs63751255, rs281864938, rs63751202, rs63750726, rs63751310, rs63749900, rs587778964, rs267607879, rs267607878, rs587778966, rs267607883, rs267607887, rs63750061, rs63750663, rs587778968, rs587778971, rs63750809, rs63749867, rs63750864, rs587778972, rs63751275, rs267607718, rs267607722, rs63750769, rs267607717, rs587778973, rs267607716, rs267607720, rs63749995, rs63750859, rs587778975, rs63750114, rs587778976, rs63750603, rs267607889, rs267607723, rs63750561, rs63750499, rs63751642, rs63751022, rs587778981, rs63750971, rs267607898, rs267607906, rs267607903, rs587778989, rs587778992, rs267607894, rs267607901, rs267607892, rs63750437, rs587778997, rs587778998, rs63750005, rs63750641, rs63751421, rs11541859, rs63750266, rs111052004, rs267607726, rs267607727, rs63750453, rs267607734, rs267607735, rs63751665, rs267607736, rs267607732, rs63749816, rs63750539, rs267607739, rs587779006, rs587779008, rs267607745, rs267607742, rs63751595, rs267607743, rs587779010, rs587779012, rs63750057, rs63749818, rs63751124, rs587779014, rs587779015, rs63749820, rs63751302, rs267607750, rs267607751, rs267607749, rs63750891, rs63749959, rs63749804, rs267607765, rs267607760, rs587779021, rs267607759, rs63750515, rs587779023, rs63751021, rs63751480, rs267607772, rs267607773, rs587779024, rs63751653, rs587779027, rs267607767, rs587779029, rs63750706, rs63750385, rs267607774, rs267607778, rs267607780, rs587779034, rs63751711, rs267607784, rs587779035, rs63750823, rs63750822, rs267607787, rs63750303, rs63749839, rs63749827, rs267607789, rs267607790, rs267607791, rs267607786, rs267607771, rs267607795, rs267607794, rs267607788, rs267607799, rs267607801, rs587779045, rs63750034, rs587779047, rs63750216, rs63751707, rs63751598, rs267607803, rs267607777, rs63750144, rs267607805, rs63750547, rs63750489, rs63750993, rs587779054, rs63751259, rs63749926, rs63750796, rs587779058, rs63750745, rs63750582, rs180177084, rs587779866, rs200389141, rs587779950, rs587780104, rs587780183, rs587778536, rs587780683, rs587781554, rs267607712, rs587777627, rs587783057, rs730881734, rs41542214, rs730881273, rs786203456, rs786201990, rs786202767, rs748005072, rs786204317, rs786204318, rs797045117, rs63750549, rs863225383, rs863225384, rs863225373, rs863225376, rs863225377, rs863225378, rs863225379, rs863225380, rs863225381, rs63750059, rs267607823, rs864622457, rs869312767, rs869312753, rs876661059, rs876658915, rs876658923, rs876660860, rs876660822, rs876660458, rs876660214, rs876658657, rs876658247, rs876659226, rs876658821, rs876660589, rs876659068, rs876659681, rs876659608, rs878853794, rs878853778, rs878853780, rs878853785, rs886039423, rs886039424, rs1057517543, rs1057517541, rs756843954, rs1057517617, rs1057517558, rs1057519256, rs1060500689, rs764085979, rs1060500707, rs1060500699, rs1060500706, rs1060500703, rs1064795341, rs1064793607, rs1064794348, rs1064795441, rs1064794373, rs1064793172, rs1064794122, rs1064795515, rs1064794331, rs63750978, rs1114167435, rs1553641362, rs63751448, rs1553648029, rs1553648058, rs587778903, rs1553653237, rs1553664353, rs267607744, rs1553647995, rs1553648047, rs1553653084, rs1553663750, rs1553664436, rs1553488015, rs1553637293, rs63750310, rs63750443, rs63751596, rs1553646681, rs550890395, rs1064796057, rs1553642079, rs1553648023, rs587782087, rs746536721, rs1553653037, rs1248251121, rs1553646602, rs1434898623, rs1553665683, rs1553648068, rs1553645331, rs1553644123, rs1553658246, rs1553651299, rs1553648149, rs1553663159, rs1302248679, rs1553664119, rs1553658009, rs1553665977, rs1416171624, rs1553663834, rs1553664617, rs1553664702, rs1553647969, rs1553648040, rs1437454428, rs1553641273, rs63751101, rs1553646764, rs1553648225, rs1554082118, rs1553648201, rs1553638868, rs1553665866, rs376736188, rs1553642707, rs1553645226, rs1553652883, rs63751435, rs1553653115, rs1553653195, rs63750300, rs1553662622, rs1553658104, rs1553648220, rs1559544064, rs63750584, rs267608083, rs1559551570, rs1559575107, rs1559553501, rs1565986506, rs1559524405, rs1559553492, rs1559554339, rs1559588540, rs1559558071, rs761329565, rs1559521039, rs1559574795, rs1567221417, rs1559578422, rs1481129490, rs1570714352, rs779783209, rs1575376830, rs1575469070, rs1575537843, rs1575620443, rs1575621506, rs587779022, rs1575414904, rs1575449093, rs1575469505, rs1575536254, rs1575537933, rs1575632112, rs1575639851, rs1575441094, rs1575449402, rs267607831, rs2081922847, rs2083403132, rs2085415927, rs2085469647, rs2043913790, rs147542208
Coronary artery disease	Coronary Artery Disease	rs137852988, rs121918313, rs-1, rs121918529, rs121918531, rs137852340, rs405509, rs1555800701, rs1215189537	12669274
Tumoral calcinosis	Tumoral calcinosis, TUMORAL CALCINOSIS, HYPERPHOSPHATEMIC, FAMILIAL, TUMORAL CALCINOSIS, HYPERPHOSPHATEMIC, FAMILIAL, 1, TUMORAL CALCINOSIS, HYPERPHOSPHATEMIC, FAMILIAL, 3	rs104894343, rs104894344, rs745655924, rs137853086, rs375879489, rs761396172, rs137853087, rs137853091, rs137853088, rs137853089, rs137853090, rs766750282, rs760830864, rs786205250, rs267606841, rs1555096583, rs1220533001, rs762936774, rs775341386	17710231, 22142751
Hyperphosphatemic tumoral calcinosis	Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome	rs863224872
Hypercalciuria	Hypercalciuria, childhood idiopathic	rs-1, rs121908542, rs1588844639	20394945
Kidney disease	Kidney Diseases	rs74315342, rs749740335, rs757649673, rs112417755, rs35138315	23665422
Osteoporosis	Osteoporosis, Age-Related, Osteoporosis, Osteoporosis, Senile, Post-Traumatic Osteoporosis	rs72658152, rs72667023, rs587776916, rs72656370, rs768615287	9363890
Hypercalcemia	Hypercalcemia, Hypercalcemia, Idiopathic, of Infancy	rs876657376, rs387907322, rs777676129, rs387907323, rs114368325, rs6068812, rs387907324, rs777947329, rs201304511, rs769409705, rs200095793, rs876661338, rs1554095500, rs139763321, rs774432244, rs781367354	17710231, 20394945

Unknown
Disease name	Disease term	dbSNP ID	References
Arteriosclerosis	Arteriosclerosis		9363890
Coronary arteriosclerosis	Coronary Arteriosclerosis		12669274
Dermatologic disorders	Dermatologic disorders		9363890
Hyperphosphatemia	Hyperphosphatemia (disorder)		17710231
Learning disorders	Learning Disorders, Adult Learning Disorders, Learning Disturbance, Learning Disabilities		25309793
Memory disorders	Memory Disorders		25550330, 25309793
Age-related memory disorders	Age-Related Memory Disorders		25550330, 25309793
Milk-alkali syndrome	Milk-Alkali Syndrome		17710231
Premature aging	Premature aging syndrome		9363890, 25550330
Subfertility	Subfertility		9363890