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EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis

Adamo, Christin S. ; Beyens, Aude ; Schiavinato, Alvise ; Keene, Douglas R. ; Tufa, Sara F. ; Mörgelin, Matthias LU ; Brinckmann, Jürgen ; Sasaki, Takako ; Niehoff, Anja and Dreiner, Maren , et al. (2022) In American Journal of Human Genetics 109(12). p.2230-2252
Abstract

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface 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 elastogenesis, reduced collagen crosslinking, and aberrant growth factor... (More)

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface 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 elastogenesis, 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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aortic aneurysm, arterial tortuosity, collagen, cutis laxa, EFEMP2, elastic fiber, EMILIN1, extracellular matrix, fracture, LOX
in
American Journal of Human Genetics
volume
109
issue
12
pages
23 pages
publisher
Cell Press
external identifiers
  • scopus:85143380065
  • pmid:36351433
ISSN
0002-9297
DOI
10.1016/j.ajhg.2022.10.010
language
English
LU publication?
yes
id
95bfae77-82d9-44b3-91fd-54224026d2fb
date added to LUP
2022-12-23 09:22:51
date last changed
2024-10-02 11:29:36
@article{95bfae77-82d9-44b3-91fd-54224026d2fb,
  abstract     = {{<p>EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface 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 elastogenesis, 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.</p>}},
  author       = {{Adamo, Christin S. and Beyens, Aude and Schiavinato, Alvise and Keene, Douglas R. and Tufa, Sara F. and Mörgelin, Matthias and Brinckmann, Jürgen and Sasaki, Takako and Niehoff, Anja and Dreiner, Maren and Pottie, Lore and Muiño-Mosquera, Laura and Gulec, Elif Yilmaz and Gezdirici, Alper and Braghetta, Paola and Bonaldo, Paolo and Wagener, Raimund and Paulsson, Mats and Bornaun, Helen and De Rycke, Riet and De Bruyne, Michiel and Baeke, Femke and Devine, Walter P. and Gangaram, Balram and Tam, Allison and Balasubramanian, Meena and Ellard, Sian and Moore, Sandra and Symoens, Sofie and Shen, Joseph and Cole, Stacey and Schwarze, Ulrike and Holmes, Kathryn W. and Hayflick, Susan J. and Wiszniewski, Wojciech and Nampoothiri, Sheela and Davis, Elaine C. and Sakai, Lynn Y. and Sengle, Gerhard and Callewaert, Bert}},
  issn         = {{0002-9297}},
  keywords     = {{aortic aneurysm; arterial tortuosity; collagen; cutis laxa; EFEMP2; elastic fiber; EMILIN1; extracellular matrix; fracture; LOX}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{2230--2252}},
  publisher    = {{Cell Press}},
  series       = {{American Journal of Human Genetics}},
  title        = {{EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis}},
  url          = {{http://dx.doi.org/10.1016/j.ajhg.2022.10.010}},
  doi          = {{10.1016/j.ajhg.2022.10.010}},
  volume       = {{109}},
  year         = {{2022}},
}