KLHL24 Gene

KLHL24 (KLHL24 is the acronym for Kelch Like Family Member 24) is a protein coding gene located on chromosome 3q27.1. KLHL24 is a member of the Kelch-like family of proteins that function as substrate-specific adaptors for cullin E3 ubiquitin ligases. The encoded protein is necessary for maintaining the balance between stability and degradation of intermediate filaments, a process that is essential for the integrity of the skin as well as the heart. KLHL24 is part of the BCR(KLHL24)-E3 ubiquitin ligase complex. This complex mediates the ubiquitination of KRT14, thereby controlling its levels during keratinocyte differentiation. KLHL24 specifically reduces kainate receptor-mediated currents in hippocampal neurons, most likely by modulating channel properties.

Diseases associated with KLHL24 include:

• Variants of epidermolysis bullosa simplex (see below hereditary epidermolyses).
• Hereditary hypertrophic cardiomyopathy (HCM): this form of cardiomyopathy is the most common hereditary cardiovascular disease. >1400 mutations in >27 gene loci are now known. Mutations in KLHL24 can cause HCM in humans.

Variations in the translation initiation codon of this gene have been found, resulting in an N-terminally truncated but more stable protein due to loss of autobiquitination function. The more stable mutant protein leads to increased ubiquitin formation and degradation of keratin 14, resulting in skin fragility and epidermolysis bullosa.

Fouad S et al (2019) Cullin ring ubiquitin ligases (CRLs) in cancer: responses to ionizing radiation (IR) treatment. Front Physiol 10:1144

Hedberg-Oldfors C et al. (2019) Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24. Hum Mol Genet 28:1919-1929.

Lin Z et al (2016) Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility. Nat Genet 48:1508-1516.