Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24

KLHL24: Beyond Skin Fragility

“…However, other groups (He et al, 2016;Lee et al, 2017) showed positive, although disorganized, staining of K14 in skin biopsy samples and increased amounts of K14 and K5 in keratinocyte cultures from patients with mutated KLHL24, suggesting that the mutated proteins have a lower ability to promote keratin 14 degradation than the normal molecule, similar to the accumulation of undesired substrates seen in deficiencies of other members of the Kelch superfamily (Gupta and Beggs, 2014). We observed significantly reduced K14 expression the neonatal healthy-appearing skin of a KLHL24-mutated patient, and staining of skin at the age of 14 years showed normal K14 (Yenamandra et al, 2018), suggesting that KLHL24 regulation of K14 turnover may be more impaired during epidermal proliferation such as with body growth. The reported burnlike scars in patients with EBS due to KLHL24 mutations are not seen in EBS caused by mutations in other EBSassociated genes (Alkhalifa et al, 2018;He et al, 2016;Yenamandra et al, 2018).…”

“…We observed significantly reduced K14 expression the neonatal healthy-appearing skin of a KLHL24-mutated patient, and staining of skin at the age of 14 years showed normal K14 (Yenamandra et al, 2018), suggesting that KLHL24 regulation of K14 turnover may be more impaired during epidermal proliferation such as with body growth. The reported burnlike scars in patients with EBS due to KLHL24 mutations are not seen in EBS caused by mutations in other EBSassociated genes (Alkhalifa et al, 2018;He et al, 2016;Yenamandra et al, 2018). Additionally, Yenamandra et al reported an abnormal basement membrane structure with thickening and thinning of the lamina densa with re-duplications and blind offshoots typically encountered in poikiloderma, indicating other or additional skin pathology besides keratin filament fragility in basal keratinocytes in the case of perturbed KLHL24.…”

“…KLHL24 is widely expressed in tissues other than skin, including brain, heart, skeletal muscle, kidney, liver, lung, and pancreas, with many tissues showing higher expression than skin (He et al, 2016;Lin et al, 2016 In addition to an earlier case report (Yenamandra et al, 2018), Schwieger-Briel et al (2018) report a cohort of 20 EBS patients with the known KLHL24 missense mutations in which a strikingly high percentage of patients suffered from dilated cardiomyopathy (DCM): 85% had evidence of cardiac involvement with either elevated cardiac biomarkers or proven DCM (8/20 patients, 40%), leading to death at an early age in two patients. DCM may be a final common pathway of various cardiac pathologies; however, in all reported patients no signs of other causes were found.…”

“…In 2016, Lin et al (2016) and He et al (2016), using whole-exome sequencing, discovered dominant acting point mutations in the start codon of KLHL24 caused basal cell skin fragility. Since then, several other patients with basal EBS caused by KLHL24 mutations, all affecting the same start codon, have been reported (Alkhalifa et al, 2018;Lee et al, 2017;Yenamandra et al, 2018). KLHL24, unlike K5 and K14, is not a structural protein.…”

“…Another interesting observation is the cell membrane localization and colocalization of KLHL24 with desmoplakin in keratinocytes and cardiomyocytes (He et al, 2016;Yenamandra et al, 2018), because mutations in the desmosomal protein desmoplakin are associated with DCM, either nonsyndromic or syndromic, in Carvajal syndrome, as well.…”