All EBS cases reported so far harboured recurrent monoallelic mutations in the KLHL24 translation initiation codon, c.1A>G, c.1A>T, c.2T>C, c.2T>G, c.3G>T, c.3G>A, with a high rate of de novo mutations. These mutations do not alter mRNA levels and gene expression, but a transcription initiation site located 29 codons downstream is used. The N-terminal truncated KLHL24 is more stable than its wild type counterpart due to abolished autoubiquitination. KLHL24 is a cullin 3-Rbx1 ubiquitin ligase substrate receptor for keratin 14. The ultrastructural pathology of EBS-KLHL24 includes paucity of intermediate filaments, numerous autophagosomes and autolysosomes and prominent mitochondria. Thus, KLHL24 gain-of-function mutations were proposed to lead to increased keratin 14 degradation and skin fragility. Although this straightforward hypothesis seems very attractive, other studies did not observe any significant reduction of the abundance of keratin 14 in the skin and keratinocytes of patients. New reports are expected with high interest to clarify this controversy.
KLHL24 is expressed in multiple tissues, such as heart, brain, liver, skeleton muscle, kidney, pancreas, placenta, lung and peripheral blood, and in the main skin cell types – keratinocytes, fibroblasts and melanocytes. In neurons, KLHL24 binds to the C-terminal domain of the kaianate receptor GluR6 and regulates its function by interacting with PICK1 (protein interacting with protein kinase C, alpha). Loss-of-function KLHL24 mutations lead to accumulation of intermediate filaments in the heart and skeletal muscle and accumulation of desmin. In a zebra fish model klhl24a has a role during heart development, especially in the formation of a functional ventricle.
All known EBS mutations are in the translation initiation codon of KLHL24. Therefore, direct sequencing of the corresponding exon of the gene is recommended. KLHL24 should be included in NGS targeted multigene panels for epidermolysis bullosa and for cardiomyopathy.