KL (klotho; HGNC:6344, NCBI Gene ID 9365) is a human locus mapped to chromosome band 13q13.1 that encodes single-pass transmembrane Alpha-Klotho co-receptor (1,012 aa; 130 kDa) & shed soluble endocrine s-Klotho. KL acts in obligate FGF23-FGFR1c renal phosphate/vitamin D co-receptor; soluble inhibition of IGF1R, Wnt & TGFB1, together with FGF21 (Endocrine Fibroblast Growth Factor 21 Gene), IGF1R (IGF-1 Receptor Gene), and VDR (Vitamin D Receptor Gene). Encodes alpha-Klotho, the renal FGF23 co-receptor and circulating longevity hormone regulating phosphate homeostasis and cognitive resilience.
Genomic Organization & Cytogenetic Locus: 5-exon gene on chromosome 13q13.1 named after the Greek Fate who spins the thread of life (identified in 1997 by Makoto Kuro-o and colleagues, whose klotho-deficient mice showed an ageing-like syndrome), encoding a 1,012-amino-acid type I transmembrane protein with two large extracellular glycosidase-like domains (KL1 and KL2) that is cleaved at the cell surface by ADAM10 and ADAM17 secretases to release soluble 130 kDa endocrine alpha-Klotho into blood, urine, and cerebrospinal fluid.
Cellular & Tissue Expression Profile: Expressed at highest levels in renal distal and proximal convoluted tubule epithelial cells, the choroid plexus epithelium of the brain ventricles, and parathyroid gland chief cells.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Membrane-bound alpha-Klotho forms an obligate binary complex with fibroblast growth factor receptor 1c (FGFR1c) that creates the high-affinity groove for bone-derived hormone FGF23—promoting renal proximal tubule phosphate excretion (by internalizing NaPi-2a/2c cotransporters) and suppressing 1,25-dihydroxyvitamin D synthesis (CYP27B1); simultaneously, shed soluble alpha-Klotho acts as an endocrine anti-aging hormone that dampens insulin/IGF-1 (IGF1R) signaling, antagonizes fibrotic Wnt and TGF-beta1 (TGFB1) pathways, activates NFE2L2 (NRF2) antioxidant defenses, and enhances hippocampal NMDAR GluN2B synaptic plasticity.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations cause severe hyperphosphatemic familial tumoral calcinosis with ectopic vascular calcification, whereas ~20–25% of humans carry a single copy of the functional KL-VS haplotype (two missense variants in exon 2: p.Phe352Val and p.Cys370Ser), which increases circulating Klotho levels, enlarges right dorsolateral prefrontal cortex volume, enhances executive cognitive function across the lifespan, and mitigates APOE4-related amyloid and tau pathology.
Therapeutic & Clinical Pharmacology: Circulating alpha-Klotho declines steeply in chronic kidney disease and chronological aging; recombinant soluble alpha-Klotho protein infusions and AAV/CRISPR transcriptional activation are in preclinical and early translational development for chronic kidney disease, vascular calcification, and neurodegenerative dementia.