Endoglin ER-retained mutants exacerbate loss of function in hereditary
hemorrhagic telangiectasia type 1 (HHT1) by exerting dominant negative
effects on the wild type allele
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant
disorder affecting 1 in 5,000-8,000 individuals. Hereditary hemorrhagic
telangiectasia type 1 (HHT1) is the most common HHT and manifests as
diverse vascular malformations ranging from mild symptoms such as
epistaxis and mucosal and cutaneous telangiectases to severe
arteriovenous malformations (AVMs) in the lungs, brain or liver. HHT1 is
caused by heterozygous mutations in the ENG gene, which encodes
endoglin, the TGFb homodimeric coreceptor. It was previously shown that
some endoglin HHT1-causing variants failed to traffic to the plasma
membrane due to their retention in the endoplasmic reticulum (ER) and
consequent degradation by ER-associated degradation (ERAD). Endoglin is
a homodimer formed in the ER, and we therefore hypothesized that mixed
heterodimers might form between ER-retained variants and WT protein,
thus hampering its maturation and trafficking to the plasma membrane
causing dominant negative effects. Indeed, HA-tagged ER-retained mutants
formed heterodimers with Myc-tagged WT Endoglin. Moreover, variants
L32R, V105D, P165L, I271N and C363Y adversely affected the trafficking
of WT endoglin by reducing its maturation and plasma membrane
localization. These results strongly suggest dominant negative effects
exerted by these ER-retained variants aggravating endoglin loss of
function in patients expressing them in the heterozygous state with the
WT allele. Moreover, this study may explain some of the variability
observed among HHT1 patients due to the additional loss of function
exerted by the dominant negative effects in addition to that due to
haploinsufficiency. These findings might also have implications for some
of the many conditions impacted by ERAD.