LB732 Intravenous gentamicin therapy in adult junctional and recessive dystrophic Epidermolysis Bullosa with nonsense mutations does not result in sustained clinical improvement

Abstract

The term "cavernous hemangioma" has been used to describe vascular anomalies with histology featuring dilated vascular spaces, vessel walls consisting mainly of fibrous stromal bands lined by a layer of flattened endothelial cells, and an irregular outer rim of interrupted smooth muscle cells. Hepatic hemangiomas (HH) and cutaneous venous malformations (cVM) share this histologic pattern, and we examined lesions in both tissues to identify genetic drivers. Paired wholeexome sequencing of lesional tissue and normal liver from HH subjects revealed a recurrent GJA4 c.121G>T, p.Gly41Cys somatic mutation in 4 of 5 unrelated cases, and targeted sequencing in paired tissue from 9 additional HH subjects identified the same mutation in 8. In cutaneous lesions, paired targeted sequencing in 5 cVMs and normal epidermis, found the same GJA4 c.121G>T, p.Gly41Cys somatic mutation in 3. GJA4 encodes gap junction protein alpha 4, also called connexin 37 (Cx37), and the p.Gly41Cys mutation falls within the first transmembrane domain at a residue highly conserved among vertebrates. We investigated the impact of the Cx37 mutant via lentiviral transduction of primary human endothelial cells. We found that the mutant induced changes in cell morphology and led to non-canonical activation of SGK1, a serine/ threonine kinase known to regulate cell proliferation and apoptosis. Treatment with spironolactone, an inhibitor of angiogenesis, suppressed SGK1 activation and reversed changes in cell morphology. These findings identify a recurrent somatic GJA4 c.121G>T mutation as a driver of hepatic and cutaneous venous malformations, revealing a new pathway for vascular anomalies, with spironolactone a potential pathogenesis-based therapy. LB732Intravenous gentamicin therapy in adult junctional and recessive dystrophic Epidermolysis Bullosa with nonsense mutations does not result in sustained clinical improvement