New mechanistic insights to PLOD1-mediated human vascular disease.

ABSTRACT: Heritable thoracic aortic disease and familial thoracic aortic aneurysm/dissection are important causes of human morbidity/mortality, most without identifiable genetic cause. In a family with familial thoracic aortic aneurysm/dissection, we identified a missense p. (Ser178Arg) variant in PLOD1 segregating with disease, and evaluated PLOD1 enzymatic activity, collagen characteristics and in human aortic vascular smooth muscle cells, studied the effect on function. Comparison with homologous PLOD3 enzyme indicated that the pathogenic variant may affect the N-terminal glycosyltransferase domain, suggesting unprecedented PLOD1 activity. In vitro assays demonstrated that wild-type PLOD1 is capable of processing UDP-glycan donor substrates, and that the variant affects the folding stability of t

SUBMITTER: Koenig SN 

PROVIDER: S-EPMC8671190 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature