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

Am J Hum Genet. 2018 Apr 5;102(4):696-705. doi: 10.1016/j.ajhg.2018.02.018.

Patrick R Blackburn ¹, Zhi Xu ², Kathleen E Tumelty ³, Rose W Zhao ³, William J Monis ³, Kimberly G Harris ⁴, Jennifer M Gass ⁵, Margot A Cousin ⁶, Nicole J Boczek ¹, Mario V Mitkov ⁷, Mark A Cappel ⁷, Clair A Francomano ⁸, Joseph E Parisi ⁹, Eric W Klee ¹⁰, Eissa Faqeih ¹¹, Fowzan S Alkuraya ¹², Matthew D Layne ³, Nazli B McDonnell ¹³, Paldeep S Atwal ¹⁴

Affiliations

1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
2 Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
3 Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
4 Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA.
5 Center for Individualized Medicine, Mayo Clinic, Jacksonville, FL 32224, USA.
6 Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
7 Department of Dermatology, Mayo Clinic, Jacksonville, FL 32224, USA.
8 Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA; Greater Baltimore Medical Center, Towson, MD 21204, USA.
9 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
10 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
11 Department of Pediatric Specialties, Children's Hospital, King Fahad Medical City, Riyadh 12231, Saudi Arabia.
12 Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh 12371, Saudi Arabia; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia; King Abdullah University of Science and Technology (KAUST), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia.
13 Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA; Veteran's Administration, Eastern Colorado Health System, Denver, CO 80220, USA. Electronic address: [email protected].
14 Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA; Center for Individualized Medicine, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: [email protected].

PMID: 29606302 DOI: 10.1016/j.ajhg.2018.02.018

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.Arg440Serfs^∗3]) 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 bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

Keywords

ACLP; AEBP1; Aebp1-null mice; Ehlers-Danlos syndrome; aortic carboxypeptidase-like protein; collagen polymerization; connective tissue disorders; discoidin domain; exome sequencing; extracellular matrix.

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