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

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 RyckeMichiel 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

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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.

Original language	English (US)
Pages (from-to)	2230-2252
Number of pages	23
Journal	American Journal of Human Genetics
Volume	109
Issue number	12
DOIs	https://doi.org/10.1016/j.ajhg.2022.10.010
State	Published - Dec 1 2022

Keywords

EFEMP2
EMILIN1
LOX
aortic aneurysm
arterial tortuosity
collagen
cutis laxa
elastic fiber
extracellular matrix
fracture

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2022.10.010

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Adamo, C. S., Beyens, A., Schiavinato, A., Keene, D. R., Tufa, S. F., Mörgelin, M., Brinckmann, J., Sasaki, T., Niehoff, A., Dreiner, M., Pottie, L., Muiño-Mosquera, L., Gulec, E. Y., Gezdirici, A., Braghetta, P., Bonaldo, P., Wagener, R., Paulsson, M., Bornaun, H., ... Callewaert, B. (2022). EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis. American Journal of Human Genetics, 109(12), 2230-2252. https://doi.org/10.1016/j.ajhg.2022.10.010

Adamo, CS, Beyens, A, Schiavinato, A, Keene, DR, Tufa, SF, Mörgelin, M, Brinckmann, J, Sasaki, T, Niehoff, A, Dreiner, M, Pottie, L, Muiño-Mosquera, L, Gulec, EY, Gezdirici, A, Braghetta, P, Bonaldo, P, Wagener, R, Paulsson, M, Bornaun, H, De Rycke, R, De Bruyne, M, Baeke, F, Devine, WP, Gangaram, B, Tam, A, Balasubramanian, M, Ellard, S, Moore, S, Symoens, S, Shen, J, Cole, S, Schwarze, U, Holmes, KW , Hayflick, SJ , Wiszniewski, W, Nampoothiri, S, Davis, EC, Sakai, LY, Sengle, G & Callewaert, B 2022, 'EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis', American Journal of Human Genetics, vol. 109, no. 12, pp. 2230-2252. https://doi.org/10.1016/j.ajhg.2022.10.010

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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 = "Publisher Copyright: {\textcopyright} 2022 American Society of Human Genetics",

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doi = "10.1016/j.ajhg.2022.10.010",

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T1 - EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis

AU - Adamo, Christin S.

AU - Beyens, Aude

AU - Schiavinato, Alvise

AU - Keene, Douglas R.

AU - Tufa, Sara F.

AU - Mörgelin, Matthias

AU - Brinckmann, Jürgen

AU - Sasaki, Takako

AU - Niehoff, Anja

AU - Dreiner, Maren

AU - Pottie, Lore

AU - Muiño-Mosquera, Laura

AU - Gulec, Elif Yilmaz

AU - Gezdirici, Alper

AU - Braghetta, Paola

AU - Bonaldo, Paolo

AU - Wagener, Raimund

AU - Paulsson, Mats

AU - Bornaun, Helen

AU - De Rycke, Riet

AU - De Bruyne, Michiel

AU - Baeke, Femke

AU - Devine, Walter P.

AU - Gangaram, Balram

AU - Tam, Allison

AU - Balasubramanian, Meena

AU - Ellard, Sian

AU - Moore, Sandra

AU - Symoens, Sofie

AU - Shen, Joseph

AU - Cole, Stacey

AU - Schwarze, Ulrike

AU - Holmes, Kathryn W.

AU - Hayflick, Susan J.

AU - Wiszniewski, Wojciech

AU - Nampoothiri, Sheela

AU - Davis, Elaine C.

AU - Sakai, Lynn Y.

AU - Sengle, Gerhard

AU - Callewaert, Bert

PY - 2022/12/1

Y1 - 2022/12/1

N2 - 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.

AB - 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.

KW - EFEMP2

KW - EMILIN1

KW - LOX

KW - aortic aneurysm

KW - arterial tortuosity

KW - collagen

KW - cutis laxa

KW - elastic fiber

KW - extracellular matrix

KW - fracture

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DO - 10.1016/j.ajhg.2022.10.010

M3 - Article

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AN - SCOPUS:85143380065

SN - 0002-9297

VL - 109

SP - 2230

EP - 2252

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 12

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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