@article{0381a46724e44676b7d8465d977ded7e,
title = "EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis",
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 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.",
keywords = "EFEMP2, EMILIN1, LOX, aortic aneurysm, arterial tortuosity, collagen, cutis laxa, elastic fiber, extracellular matrix, fracture",
author = "Adamo, {Christin S.} and Aude Beyens and Alvise Schiavinato and Keene, {Douglas R.} and Tufa, {Sara F.} and Matthias M{\"o}rgelin and J{\"u}rgen Brinckmann and Takako Sasaki and Anja Niehoff and Maren Dreiner and Lore Pottie and Laura Mui{\~n}o-Mosquera and Gulec, {Elif Yilmaz} and Alper Gezdirici and Paola Braghetta and Paolo Bonaldo and Raimund Wagener and Mats Paulsson and Helen Bornaun and {De Rycke}, Riet and {De Bruyne}, Michiel and Femke Baeke and Devine, {Walter P.} and Balram Gangaram and Allison Tam and Meena Balasubramanian and Sian Ellard and Sandra Moore and Sofie Symoens and Joseph Shen and Stacey Cole and Ulrike Schwarze and Holmes, {Kathryn W.} and Hayflick, {Susan J.} and Wojciech Wiszniewski and Sheela Nampoothiri and Davis, {Elaine C.} and Sakai, {Lynn Y.} and Gerhard Sengle and Bert Callewaert",
note = "Funding Information: Mass spectrometric analysis and statistical evaluation was performed by Dr. Stefan M{\"u}ller (CECAD Proteomics Facility). TEM-analysis of murine samples was carried out by Beatrix Martiny, C.S.A. and G.S. in the CECAD Imaging Facility. TEM-analysis of human samples was conducted by M.D.B. F.B. A.B. and R.D.R. in the VIB-Bioimaging Core. TEM analysis of fibroblast supernatants was performed by M.M. EM analyses of biopsies from family 4 were carried out by D.R.K. We are grateful to the staff in the BioEM Lab, Biozentrum, University of Basel, and the Core Facility for Integrated Microscopy (CFIM), Panum Institute, University of Copenhagen, for providing highly innovative environments for electron microscopy. We thank Carola Alampi (BioEM lab), Mohamed Chami (BioEM lab), and Klaus Qvortrup (FCIM) for practical help with electron microscopy. Funding for this study was provided by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project numbers 397484323 (TRR 259/B09), 73111208 (SFB 829/B12), and 384170921 (FOR2722/B1 to R.W. and M.P. FOR2722/D1 to A.N. and FOR2722/C2 to G.S.). B.C. is a senior clinical investigator of the Research Foundation Flanders. This work was supported by grants of the Special Research Fund of Ghent University (grant 01N04516C and BOF21/GOA/019 to B.C.), a research grant G035620N of the Research Foundation - Flanders (FWO) to B.C. and a research grant of European Academy of Dermatology and Venereology (PPRC-2018-50) to B.C. Ghent University Hospital is a member of the European Reference Network for Skin Disorders (ERN-Skin), intellectual disability, tele-health, autism and congenital abnormalities (ERN-ITHACA) and vascular abnormalities (VascERN). The authors declare no competing interests. Funding Information: Mass spectrometric analysis and statistical evaluation was performed by Dr. Stefan M{\"u}ller (CECAD Proteomics Facility). TEM-analysis of murine samples was carried out by Beatrix Martiny, C.S.A., and G.S. in the CECAD Imaging Facility. TEM-analysis of human samples was conducted by M.D.B., F.B., A.B., and R.D.R. in the VIB-Bioimaging Core. TEM analysis of fibroblast supernatants was performed by M.M. EM analyses of biopsies from family 4 were carried out by D.R.K. We are grateful to the staff in the BioEM Lab, Biozentrum, University of Basel, and the Core Facility for Integrated Microscopy (CFIM), Panum Institute, University of Copenhagen, for providing highly innovative environments for electron microscopy. We thank Carola Alampi (BioEM lab), Mohamed Chami (BioEM lab), and Klaus Qvortrup (FCIM) for practical help with electron microscopy. Funding for this study was provided by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project numbers 397484323 ( TRR 259/B09 ), 73111208 ( SFB 829/B12 ), and 384170921 ( FOR2722/B1 to R.W. and M.P., FOR2722/D1 to A.N., and FOR2722/C2 to G.S.). B.C. is a senior clinical investigator of the Research Foundation Flanders . This work was supported by grants of the Special Research Fund of Ghent University (grant 01N04516C and BOF21/GOA/019 to B.C.), a research grant G035620N of the Research Foundation - Flanders ( FWO ) to B.C., and a research grant of European Academy of Dermatology and Venereology ( PPRC-2018-50 ) to B.C. Ghent University Hospital is a member of the European Reference Network for Skin Disorders (ERN-Skin), intellectual disability, tele-health, autism and congenital abnormalities (ERN-ITHACA) and vascular abnormalities (VascERN). Publisher Copyright: {\textcopyright} 2022 American Society of Human Genetics",
year = "2022",
month = dec,
day = "1",
doi = "10.1016/j.ajhg.2022.10.010",
language = "English (US)",
volume = "109",
pages = "2230--2252",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "12",
}