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 bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

Heritable disorders of connective tissue: Description of a data repository and initial cohort characterization

“…A molecular diagnosis was used for the arthrochalasia and kyphoscoliotic types. Some patients had features overlapping with two or more types of EDS, and classification proved to be difficult in those cases, and such patients were diagnosed as “EDS, unclassified.” If we had a clinical impression of EDS but they did not meet the diagnostic criteria for any of the known types, we assigned a diagnosis of “EDS, unclassified.” Participants in this group may be reclassified as new genetic causes are found (Blackburn et al, ).…”

COL1‐related overlap disorder: A novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers‐Danlos syndrome overlap

“…The 2017 classification identifies 13 different clinical types due to abnormalities in 19 genes 1. A fourteenth variant similar to classical EDS and showing an autosomal recessive inheritance has been subsequently associated with biallelic AEBP1 variants 22. The identification of further novel genes and/or genotype-phenotype correlations is very probably to happen as more patients clinically diagnosed with EDS and related disorders receive molecular confirmation.The clinical manifestations of EDS are broad and often overlap with closely related disorders, such as some bone dysplasias, cutis laxa syndromes, hereditary myopathies, and TGFbeta-related disorders 23.…”

A single cell transcriptional atlas of early synovial joint development

“…Ebf1 --expressed in presumptive tendons surrounding chondrogenic condensation (Mella et al 2004)) and other factors that have not previously been implicated in this process such as Dlx5, Dlx6, which are expressed in presumptive elbow joint and involved in osteogenesis (Ferrari and Kosher 2006; Lee et al 2003). The predicted regulators of the final stage included TFs associated with inflammatory response: Cebpd, Egr1; osteogenesis: Sp7, Cbfb (Lien et al 2007), and tendon development: Klf10 (McConnell and Yang 2010), Klf2, Klf4, Aebp1 (Blackburn et al 2018), Ddit3 (Caterson and Melrose 2018), and Bhlhe40 (Peffers et al 2015) ( Fig 6K ). In summary, the development of fibrous components of the synovial joint, particularly tendon/ligament, is characterized by the ordered loss of chondrogenic gene expression programs followed by the upregulation of tendon/ligament expression programs.…”