Kelch-like protein 3 explained

Kelch-like protein 3 is a protein in humans that is encoded by the KLHL3 gene.^[1] Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Function

This gene is ubiquitously expressed and encodes a full-length protein which has an N-terminal BTB domain followed by a BACK domain and six kelch-like repeats in the C-terminus. These kelch-like repeats promote substrate ubiquitination of bound proteins via interaction of the BTB domain with the CUL3 (cullin 3) component of a cullin-RING E3 ubiquitin ligase (CRL) complex.^[1]

Clinical significance

Pseudohypoaldosteronism Type 2D

Mutations in this gene cause pseudohypoaldosteronism type IID (PHA2D);^{[2] [3]} a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis.^[1]

Ischemic Stroke

A machine learning model identified the KLHL3 gene as a key gene in the occurrence and progression of ischemic stroke.^[4]

Further reading

• Hirosawa M, Nagase T, Ishikawa K, Kikuno R, Nomura N, Ohara O . Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain . DNA Research . 6 . 5 . 329–336 . October 1999 . 10574461 . 10.1093/dnares/6.5.329 . free .
• Yeo A, Samways DS, Fowler CE, Gunn-Moore F, Henderson G . Coincident signalling between the Gi/Go-coupled delta-opioid receptor and the Gq-coupled m3 muscarinic receptor at the level of intracellular free calcium in SH-SY5Y cells . Journal of Neurochemistry . 76 . 6 . 1688–1700 . March 2001 . 11259487 . 10.1046/j.1471-4159.2001.00185.x . 2755275 .
• Mizutani A, Fukuda M, Ibata K, Shiraishi Y, Mikoshiba K . SYNCRIP, a cytoplasmic counterpart of heterogeneous nuclear ribonucleoprotein R, interacts with ubiquitous synaptotagmin isoforms . The Journal of Biological Chemistry . 275 . 13 . 9823–9831 . March 2000 . 10734137 . 10.1074/jbc.275.13.9823 . free .
• Lai F, Orelli BJ, Till BG, Godley LA, Fernald AA, Pamintuan L, Le Beau MM . Molecular characterization of KLHL3, a human homologue of the Drosophila kelch gene . Genomics . 66 . 1 . 65–75 . May 2000 . 10843806 . 10.1006/geno.2000.6181 .

Notes and References

1. Web site: Entrez Gene: Kelch-like 3 (Drosophila) . 2012-04-26 .
2. Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, Beaurain G, Bonnefond A, Sand O, Simian C, Vidal-Petiot E, Soukaseum C, Mandet C, Broux F, Chabre O, Delahousse M, Esnault V, Fiquet B, Houillier P, Bagnis CI, Koenig J, Konrad M, Landais P, Mourani C, Niaudet P, Probst V, Thauvin C, Unwin RJ, Soroka SD, Ehret G, Ossowski S, Caulfield M, Bruneval P, Estivill X, Froguel P, Hadchouel J, Schott JJ, Jeunemaitre X . KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron . Nature Genetics . 44 . 4 . 609 . March 2012 . 22406640 . 10.1038/ng0512-609 . free .
3. Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G, Lebel M, Gordon RD, Semmekrot BA, Poujol A, Välimäki MJ, De Ferrari ME, Sanjad SA, Gutkin M, Karet FE, Tucci JR, Stockigt JR, Keppler-Noreuil KM, Porter CC, Anand SK, Whiteford ML, Davis ID, Dewar SB, Bettinelli A, Fadrowski JJ, Belsha CW, Hunley TE, Nelson RD, Trachtman H, Cole TR, Pinsk M, Bockenhauer D, Shenoy M, Vaidyanathan P, Foreman JW, Rasoulpour M, Thameem F, Al-Shahrouri HZ, Radhakrishnan J, Gharavi AG, Goilav B, Lifton RP . Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities . Nature . 482 . 7383 . 98–102 . January 2012 . 22266938 . 3278668 . 10.1038/nature10814 .
4. Huang D, Zhu Y, Shen J, Song C . Identification of Potential Neddylation-related Key Genes in Ischemic Stroke based on Machine Learning Methods . Molecular Neurobiology . 61 . 5 . 2530–2541 . May 2024 . 37910287 . 10.1007/s12035-023-03738-5 .