Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome

Patrick R. Blackburn; Zhi Xu; Kathleen E. Tumelty; Rose W. Zhao; William J. Monis; Kimberly G. Harris; Jennifer M. Gass; Margot A. Cousin; Nicole J. Boczek; Mario V. Mitkov; Mark A. Cappel; Clair A. Francomano; Joseph E. Parisi; Eric W. Klee; Eissa Faqeih; Fowzan S. Alkuraya; Matthew D. Layne; Nazli B. McDonnell; Paldeep S. Atwal

doi:10.1016/j.ajhg.2018.02.018

Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome

Patrick R. Blackburn, Zhi Xu, Kathleen E. Tumelty, Rose W. Zhao, William J. Monis, Kimberly G. Harris, Jennifer M. Gass, Margot A. Cousin, Nicole J. Boczek, Mario V. Mitkov, Mark A. Cappel, Clair A. Francomano, Joseph E. Parisi, Eric W. Klee, Eissa Faqeih, Fowzan S. Alkuraya, Matthew D. Layne, Nazli B. McDonnell, Paldeep S. Atwal

King Abdullah University of Science and Technology

Research output: Contribution to journal › Article › peer-review

106 Scopus citations

Abstract

AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that biallelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

Original language	English (US)
Pages (from-to)	696-705
Number of pages	10
Journal	The American Journal of Human Genetics
Volume	102
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2018.02.018
State	Published - Mar 29 2018

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: We would like to thank the subjects and their families for participating in this study. This work was made possible through support provided by the Mayo Clinic Center for Individualized Medicine (CIM) through the CIM Investigative and Functional Genomics Program. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging protocol numbers 03-AG-N330 (formerly 2003-086) and 11-AG-N079 (N.B.M. and C.A.F.), The American Heart Association grant 14GRNT18690001 (M.D.L.), and NIH grants HL078869 and HL078869S1 (M.D.L.). R.W.Z. was supported by a UROP award from Boston University. We acknowledge the support of the Saudi Human Genome Program.

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10.1016/j.ajhg.2018.02.018

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Blackburn, P. R., Xu, Z., Tumelty, K. E., Zhao, R. W., Monis, W. J., Harris, K. G., Gass, J. M., Cousin, M. A., Boczek, N. J., Mitkov, M. V., Cappel, M. A., Francomano, C. A., Parisi, J. E., Klee, E. W., Faqeih, E., Alkuraya, F. S., Layne, M. D., McDonnell, N. B., & Atwal, P. S. (2018). Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome. The American Journal of Human Genetics, 102(4), 696-705. https://doi.org/10.1016/j.ajhg.2018.02.018

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title = "Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome",

abstract = "AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that biallelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.",

author = "Blackburn, {Patrick R.} and Zhi Xu and Tumelty, {Kathleen E.} and Zhao, {Rose W.} and Monis, {William J.} and Harris, {Kimberly G.} and Gass, {Jennifer M.} and Cousin, {Margot A.} and Boczek, {Nicole J.} and Mitkov, {Mario V.} and Cappel, {Mark A.} and Francomano, {Clair A.} and Parisi, {Joseph E.} and Klee, {Eric W.} and Eissa Faqeih and Alkuraya, {Fowzan S.} and Layne, {Matthew D.} and McDonnell, {Nazli B.} and Atwal, {Paldeep S.}",

note = "KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: We would like to thank the subjects and their families for participating in this study. This work was made possible through support provided by the Mayo Clinic Center for Individualized Medicine (CIM) through the CIM Investigative and Functional Genomics Program. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging protocol numbers 03-AG-N330 (formerly 2003-086) and 11-AG-N079 (N.B.M. and C.A.F.), The American Heart Association grant 14GRNT18690001 (M.D.L.), and NIH grants HL078869 and HL078869S1 (M.D.L.). R.W.Z. was supported by a UROP award from Boston University. We acknowledge the support of the Saudi Human Genome Program.",

year = "2018",

month = mar,

day = "29",

doi = "10.1016/j.ajhg.2018.02.018",

language = "English (US)",

volume = "102",

pages = "696--705",

journal = "The American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

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Blackburn, PR, Xu, Z, Tumelty, KE, Zhao, RW, Monis, WJ, Harris, KG, Gass, JM, Cousin, MA, Boczek, NJ, Mitkov, MV, Cappel, MA, Francomano, CA, Parisi, JE, Klee, EW, Faqeih, E, Alkuraya, FS, Layne, MD, McDonnell, NB & Atwal, PS 2018, 'Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome', The American Journal of Human Genetics, vol. 102, no. 4, pp. 696-705. https://doi.org/10.1016/j.ajhg.2018.02.018

TY - JOUR

T1 - Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome

AU - Blackburn, Patrick R.

AU - Xu, Zhi

AU - Tumelty, Kathleen E.

AU - Zhao, Rose W.

AU - Monis, William J.

AU - Harris, Kimberly G.

AU - Gass, Jennifer M.

AU - Cousin, Margot A.

AU - Boczek, Nicole J.

AU - Mitkov, Mario V.

AU - Cappel, Mark A.

AU - Francomano, Clair A.

AU - Parisi, Joseph E.

AU - Klee, Eric W.

AU - Faqeih, Eissa

AU - Alkuraya, Fowzan S.

AU - Layne, Matthew D.

AU - McDonnell, Nazli B.

AU - Atwal, Paldeep S.

N1 - KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: We would like to thank the subjects and their families for participating in this study. This work was made possible through support provided by the Mayo Clinic Center for Individualized Medicine (CIM) through the CIM Investigative and Functional Genomics Program. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging protocol numbers 03-AG-N330 (formerly 2003-086) and 11-AG-N079 (N.B.M. and C.A.F.), The American Heart Association grant 14GRNT18690001 (M.D.L.), and NIH grants HL078869 and HL078869S1 (M.D.L.). R.W.Z. was supported by a UROP award from Boston University. We acknowledge the support of the Saudi Human Genome Program.

PY - 2018/3/29

Y1 - 2018/3/29

N2 - AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that biallelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

AB - AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that biallelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

UR - http://hdl.handle.net/10754/627621

UR - http://www.sciencedirect.com/science/article/pii/S0002929718300636

UR - http://www.scopus.com/inward/record.url?scp=85044258301&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2018.02.018

DO - 10.1016/j.ajhg.2018.02.018

M3 - Article

C2 - 29606302

SN - 0002-9297

VL - 102

SP - 696

EP - 705

JO - The American Journal of Human Genetics

JF - The American Journal of Human Genetics

IS - 4

ER -

Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome

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