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

Research output: Contribution to journalArticlepeer-review

93 Scopus citations


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 languageEnglish (US)
Pages (from-to)696-705
Number of pages10
JournalThe American Journal of Human Genetics
Issue number4
StatePublished - 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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