Date of Award

January 2021

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Keith A. Choate

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 single layer of flattened endothelial cells, and a variably 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 WES of lesional tissue and normal liver in HH subjects revealed a recurrent GJA4 c.121G>T, p.Gly41Cys somatic mutation in four of five 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 venous malformations and normal epidermis, found the same GJA4 c.121G>T, p.Gly41Cys somatic mutation in three. GJA4 encodes connexin 37 (Cx37), a tetraspan membrane protein, and the p.Gly41Cys mutation falls within the first transmembrane domain at a residue completely conserved among vertebrates. We interrogated the impact of the Cx37 p.Gly41Cys mutant via lentiviral transduction of primary human endothelial cells. We found that the mutant induced changes in cell morphology and activated SGK1, a serine/threonine kinase known to regulate cell proliferation and apoptosis, via non-canonical activation. Treatment with spironolactone, an inhibitor of angiogenesis, suppressed mutant SGK1 activation and reversed changes in cell morphology. These findings identify a recurrent somatic GJA4 p.Gly41Cys mutation as a driver of hepatic and cutaneous venous malformations, revealing a new pathway for vascular anomalies, with spironolactone a potential pathogenesis-based therapy.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 10/12/2023

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