The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome
Open accessAbstract
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.
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Metadata
- Authors
- 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.
- Affiliations
- Mayo Clinic (US)
- Boston University (US)
- Greater Baltimore Medical Center (US)
- King Fahd Medical City (SA)
- King Abdulaziz City for Science and Technology (SA)
- National Institutes of Health (US)
- Corresponding author
- McDonnell, Nazli B.
- Atwal, Paldeep S.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 102
- Issue
- 4
- Pages
- 696-705
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC5985336
- OpenAlex
- W2795052789
- Cited by
- 176
- References
- 33
- Citations by year
- 2026: 13 · 2025: 30 · 2024: 25 · 2023: 26 · 2022: 14 · 2021: 20 · 2020: 23 · 2019: 24 · 2018: 1
- FWCI
- 10.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
- Funders
- American Heart Association (14GRNT18690001)
- National Institutes of Health (HL078869S1, HL078869)
- National Institute on Aging (03-AG-N330, 2003-086, 11-AG-N079)
- Boston University
- Mayo Clinic
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- AEBP1, Ehlers-Danlos syndrome, collagen self-assembly, collagen fibrils, connective tissue diseases, compound heterozygosity, splice site mutation, discoidin domain, collagen polymerization, wound healing, joint laxity, skin collagen, fibroblast proliferation
- MeSH terms
- Protein Domains, Adult, Alleles, Amino Acid Sequence, Carboxypeptidases, Child, Child, Preschool, Collagen, Connective Tissue, Ehlers-Danlos Syndrome, Female, Fibroblasts, Humans, Male, Mutation, Repressor Proteins, RNA, Messenger, Skin, Young Adult
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