Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 109, Issue 12, Pages 2230-2252Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2022.10.010
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Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [397484323 ( TRR 259/B09), 73111208 ( SFB 829/B12), 384170921 (FOR2722/B1), FOR2722/D1, FOR2722/C2]
- Special Research Fund of Ghent University [01N04516C, BOF21/ GOA/019]
- Research Foundation - Flanders (FWO) [G035620N]
- European Academy of Dermatology and Venereology [PPRC-2018-50]
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EMILIN1 is a structural component of the elastic fiber network and plays a role in connecting the fibrillin microfibril scaffold and the elastin core. Loss of EMILIN1 impairs extracellular matrix deposition and LOX activity, resulting in impaired elasto-genesis, reduced collagen crosslinking, and aberrant growth factor signaling.
EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the inter-face between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elasto-genesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1-or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.
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