Cited by 176Connective tissue disorders researchDermatological and Skeletal DisordersGenomics and Rare Diseases

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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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Blackburn, Patrick R., Xu, Zhi, Tumelty, Kathleen E., Zhao, Rose W., Monis, William J., Harris, Kimberly G., Gass, Jennifer M., Cousin, Margot A., Boczek, Nicole J., Mitkov, Mario V., Cappel, Mark A., Francomano, Clair A., Parisi, Joseph E., Klee, Eric W., Faqeih, Eissa, Alkuraya, Fowzan S., Layne, Matthew D., McDonnell, Nazli B., Atwal, Paldeep S.·2018·The American Journal of Human Genetics

DOI 10.1016/j.ajhg.2018.02.018PMC PMC5985336

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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.

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Lionakis, M. S. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.737003358.793572051
Pan-Cancer Analysis Reveals AEBP1-Collagen Co-Expression and Its Potential Role in CAF-Mediated Tumor Stiffness
Sekiguchi, S., Yorozu, A., Watanabe, M., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262311474
“Several independent groups have identified bi-allelic mutations in AEBP1 as the genetic cause of a variant of Ehlers-Danlos syndrome, a systemic connective tissue disorder characterized by defective collagen assembly and impaired ECM integrity [30–33].”
Understanding Comorbidities in Hypermobile Ehlers-Danlos Syndrome: Could a Viral Infection Unmask the Disorder?Preprint
Pearson, M. L., Laraway, B. J., Elias, E. R., Bilousova, G., & Haendel, M. A. (2025) · medRxiv · doi:10.1101/2025.10.22.25338573 · Cited by 1
“Hypermobile Ehlers-Danlos Syndrome (hEDS) is the most common subtype of the Ehlers-Danlos Syndromes (EDS), a group of inherited connective tissue disorders caused by pathogenic variants affecting extracellular matrix components and collagens[1–3].”
Diagnosis of Ehlers–Danlos syndrome: data deficiency still does not allow establishment of a complete history of the disease and its pathomechanisms
Haußer, I. (2019) · British Journal of Dermatology · doi:10.1111/bjd.18373
The Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS)Preprint
Atwal, P. S., Midei, M. G., Adams, D. J., et al. (2020) · Research Square · doi:10.21203/rs.3.rs-25074/v2
Self-citation
Hypothesis paper: high prevalence of Tinel sign in hypermobile Ehlers-Danlos syndrome
Hashemi, S. S., & Knight, D. R. T. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2025.1508176
Collagen V Promotes Fibroblast Contractility, And Adhesion Formation, And Stability
Royer, S. P. (2023) · Digital Commons - Michigan Tech (Michigan Technological University) · doi:10.37099/mtu.dc.etdr/1647
Lower androgen sulfate metabolites in women with hypermobile Ehlers-Danlos syndrome may be associated with changed metabolism and disposition
Hannon, S. L., Andrews, J., & Laukaitis, C. M. (2026) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2026.107090
Putting Zebras in Plain Sight: A Focus on Ehlers-Danlos Syndrome
Cowen, L. (2023) · Inside Precision Medicine · doi:10.1089/ipm.10.06.05
Defining a Muscle Stem Cell matrisome signature: from transcriptome data to extracellular matrix niche topologyPreprint
Guillon, E., Bacar, H., Sasaki, T., Mourikis, P., & Ruggiero, F. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.10.602878
AEBP1 is a negative regulator of skeletal muscle cell differentiation in oral squamous cell carcinomaPreprint
Okazaki, F., Yorozu, A., Sekiguchi, S., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-4566879/v1
Gastrointestinal involvement in Ehlers–Danlos syndrome classical-like type 2 associated with a novel AEBP1 splice-site variant
Nakahara, H., Yamaguchi, T., Niitsu, H., et al. (2026) · Journal of Human Genetics · doi:10.1038/s10038-026-01480-z
Prevalence and management of mental health comorbidities in a German cohort of patients with Ehlers-Danlos syndromes and a generalized hypermobility spectrum disorder
Henning, M., Hock, M., Shukri, A., Löw, V., Kernich, N., Rauterberg, J., Klapproth, H., & Tantcheva-Poór, I. (2026) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-026-04242-4
“In addition, patients with cEDS show wide atrophic scarring. cEDS is due to mutations in COL5A1 , COL5A2 and rarely COL1A , while clEDS has been linked to genetic defects in TNXB and AEBP1 [3, 4].”
Bone Involvement in the Ehlers-Danlos Syndromes
Malfait, F., Syx, D., & Ishikawa, Y. (2024) · Biology of extracellular matrix · doi:10.1007/978-3-031-70835-0_3
Topical application of urolithin A activates mitophagy and enhances mitochondrial function to promote skin longevity
D’Amico, D., Faitg, J., Amaral, F., Ballihaut, C., Fouassier, A. M., Tissot, C., Rana, I., Laboureau, J., Hennighausen, N., Brandt, M., et al. (2026) · iScience · doi:10.1016/j.isci.2026.117646
The Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS)Preprint
Atwal, P. S., Midei, M. G., Adams, D. J., et al. (2020) · Research Square · doi:10.21203/rs.3.rs-25074/v1
Self-citation
A Homozygous Missense COL1A1 Variant (p.Glu684Lys) Associated with an Arthrochalasia-like Ehlers–Danlos Syndrome Phenotype: A Case Report
Маркова, Т. В., Melnik, E. A., Kurelev, M., Cherevatova, T., Nikolaeva, A., Gorodilova, D., Demina, N., & Леонидовна, Д. Е. (2026) · Genes · doi:10.3390/genes17060679
“According to the current international classification, 13 EDS subtypes are recognized, caused by pathogenic variants in 20 genes encoding structural components of connective tissue and enzymes involved in their biosynthesis and processing [2,3].”
History of Ehlers: Danlos Syndrome
DePace, N. L., Soloway, S., Yayac, M. F., & Colombo, J. (2025) · Springer eBooks · doi:10.1007/978-3-031-88769-7_2
Exploring cross-category relationships between symptoms in people with hypermobile EDS (hEDS) to identify disability patterns
Andrews, J., Harkey, Z., Mathena, S. A., Galindo, M. K., Hannon, S. L., Jesudas, R., & Laukaitis, C. M. (2026) · PLoS ONE · doi:10.1371/journal.pone.0357565
“Ehlers-Danlos Syndromes (EDS) represent a group of 13 connective tissue diseases with overlapping signs and symptoms, 12 of which are associated with pathogenic variants in specific genes and with new gene associations ongoing [1,2].”
Pediatric Musculoskeletal Medicine
Dinh, A., & Berger, A. S. (2025) · Springer eBooks · doi:10.1007/978-3-031-86057-7_25

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: Blackburn, Patrick R.
Monis, William J.
Gass, Jennifer M.
Cousin, Margot A.
Boczek, Nicole J.
Mitkov, Mario V.
Cappel, Mark A.
Francomano, Clair A.
Parisi, Joseph E.
Klee, Eric W.
Faqeih, Eissa
Alkuraya, Fowzan S.
Layne, Matthew D.
Atwal, Paldeep S.
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)
DOI: 10.1016/j.ajhg.2018.02.018
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 187 d)
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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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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