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

Christin S Adamo; Aude Beyens; Alvise Schiavinato; Douglas R Keene; Sara F Tufa; Matthias Mörgelin; Jürgen Brinckmann; Takako Sasaki; Anja Niehoff; Maren Dreiner; Lore Pottie; Laura Muiño-Mosquera; Elif Yilmaz Gulec; Alper Gezdirici; Paola Braghetta; Paolo Bonaldo; Raimund Wagener; Mats Paulsson; Helen Bornaun; Riet De Rycke; Michiel De Bruyne; Femke Baeke; Walter P Devine; Balram Gangaram; Allison Tam; Meena Balasubramanian; Sian Ellard; Sandra Moore; Sofie Symoens; Joseph Shen; Stacey Cole; Ulrike Schwarze; Kathryn W Holmes; Susan J Hayflick; Wojciech Wiszniewski; Sheela Nampoothiri; Elaine C Davis; Lynn Y Sakai; Gerhard Sengle; Bert Callewaert

doi:10.1016/j.ajhg.2022.10.010

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

Am J Hum Genet. 2022 Dec 1;109(12):2230-2252. doi: 10.1016/j.ajhg.2022.10.010. Epub 2022 Nov 8.

Authors

Christin S Adamo¹, Aude Beyens², Alvise Schiavinato³, Douglas R Keene⁴, Sara F Tufa⁴, Matthias Mörgelin⁵, Jürgen Brinckmann⁶, Takako Sasaki⁷, Anja Niehoff⁸, Maren Dreiner⁹, Lore Pottie¹⁰, Laura Muiño-Mosquera¹¹, Elif Yilmaz Gulec¹², Alper Gezdirici¹³, Paola Braghetta¹⁴, Paolo Bonaldo¹⁴, Raimund Wagener¹⁵, Mats Paulsson¹⁶, Helen Bornaun¹⁷, Riet De Rycke¹⁸, Michiel De Bruyne¹⁸, Femke Baeke¹⁸, Walter P Devine¹⁹, Balram Gangaram²⁰, Allison Tam²⁰, Meena Balasubramanian²¹, Sian Ellard²², Sandra Moore²², Sofie Symoens¹⁰, Joseph Shen²³, Stacey Cole²³, Ulrike Schwarze²⁴, Kathryn W Holmes²⁵, Susan J Hayflick²⁶, Wojciech Wiszniewski²⁶, Sheela Nampoothiri²⁷, Elaine C Davis²⁸, Lynn Y Sakai²⁶, Gerhard Sengle²⁹, Bert Callewaert³⁰

Affiliations

¹ Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
² Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Department of Dermatology, Ghent University Hospital, 9000 Ghent, Belgium.
³ Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Istituto Di Patalogia Clinica, Azienda Sanitaria Universitaria Integrata di Udine (ASUID), 33100 Udine, Italy.
⁴ Research Division, Shriners Hospital for Children, Portland, OR 97239, USA.
⁵ Division of Infection Medicine, Department of Clinical Sciences, Lund University, 22242 Lund, Sweden; Colzyx AB, 22363 Lund, Sweden.
⁶ Department of Dermatology and Institute of Virology and Cell Biology, University of Lübeck, 23562 Lübeck, Germany.
⁷ Department of Biochemistry II, Faculty of Medicine, Oita University, Oita 870-1192, Japan.
⁸ Cologne Center for Musculoskeletal Biomechanics (CCMB), Medical Faculty and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Institute of Biomechanics and Orthopaedics, German Sport University Cologne, 50933 Cologne, Germany.
⁹ Institute of Biomechanics and Orthopaedics, German Sport University Cologne, 50933 Cologne, Germany.
¹⁰ Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.
¹¹ Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Pediatric Cardiology, Ghent University Hospital, 9000 Ghent, Belgium.
¹² Department of Medical Genetics, Istanbul Medeniyet University Medical School, 34720 Istanbul, Turkey; Department of Medical Genetics, Istanbul Goztepe Prof. Dr. Suleyman Yalcin City Hospital, 34722 Istanbul, Turkey.
¹³ Department of Medical Genetics, Basaksehir Cam and Sakura City Hospital, 34480 Istanbul, Turkey.
¹⁴ Department of Molecular Medicine, University of Padova, 35131 Padova, Italy.
¹⁵ Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
¹⁶ Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Center for Musculoskeletal Biomechanics (CCMB), Medical Faculty and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
¹⁷ Department of Pediatric Cardiology, Kanuni Sultan Suleyman Research and Training Hospital, 34303 Istanbul, Turkey.
¹⁸ Department of Biomedical Molecular Biology Ghent University, 9000 Ghent, Belgium; VIB Center for Inflammation Research and BioImaging Core, VIB, 9052 Ghent, Belgium.
¹⁹ Department of Pathology, University of California San Francisco, San Francisco, CA 94115, USA.
²⁰ Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158, USA.
²¹ Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield S10 2TH, UK; Department of Oncology and Metabolism, The University of Sheffield, Sheffield S10 2TN, UK; Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, UK.
²² Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
²³ Division of Genomic Medicine, Department of Pediatrics, MIND Institute, University of California Sacramento, Sacramento, CA 95817, USA.
²⁴ Departments of Pathology and Medicine (Medical Genetics), University of Washington, Seattle, WA, USA.
²⁵ Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
²⁶ Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
²⁷ Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, Cochin, Kerala 682041, India.
²⁸ Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada.
²⁹ Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Center for Musculoskeletal Biomechanics (CCMB), Medical Faculty and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. Electronic address: gsengle@uni-koeln.de.
³⁰ Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium. Electronic address: bert.callewaert@ugent.be.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Diseases, Metabolic*
Collagen / genetics
Cutis Laxa* / genetics
Elastin / metabolism
Extracellular Matrix Proteins / metabolism
Humans
Mice

Substances

Collagen
Elastin
elastin microfibril interface located protein
Extracellular Matrix Proteins

Supplementary concepts

Arterial Tortuosity Syndrome