AEBP1 – Ehlers-Danlos Syndrome

Recent studies have demonstrated a robust association between recessive variants in AEBP1 and a clinically distinct form of Ehlers-Danlos syndrome. Multiple independent case reports and multi‐patient studies have identified pathogenic variants in AEBP1 in patients presenting with generalized joint hypermobility, skin hyperextensibility with atrophic scars, and other connective tissue abnormalities (PMID:30759870).

Genetic evidence supports an autosomal recessive inheritance pattern, as affected patients typically harbor biallelic mutations including missense, frameshift, and splice‐site variants. Notably, the variant c.1925T>C (p.Leu642Pro) has been repeatedly reported in a patient whose clinical findings were consistent with a classical EDS diagnosis (PMID:30759870). Segregation analyses in several families further affirm the pathogenicity, with multiple affected relatives confirmed to carry the disease‐associated alleles.

In addition to case reports, larger multi‐patient studies have broadened the mutational spectrum of AEBP1. These studies reported additional variants such as c.2123_2124del (p.Val708AlafsTer5) and compound heterozygous alterations that correlate with a range of connective tissue manifestations. The cumulative evidence across unrelated probands and segregating families fulfills key ClinGen criteria for a strong gene‐disease association (PMID:36553625).

Functional and experimental studies contribute to understanding the mechanism of pathogenicity. In vitro assays confirm that AEBP1 is critical for extracellular matrix integrity by modulating collagen polymerization and fibrillogenesis. Experimental data from both cellular models and animal studies further underscore that loss‐of‐function of AEBP1 impairs normal collagen assembly, which is consistent with the clinical phenotype observed in patients (PMID:29606302).

It is noteworthy that while the genetic evidence is strong, functional studies—such as those demonstrating altered DNA binding and transcriptional repression by AEBP1—add a moderate layer of experimental support. This integration of genetic and functional data not only reinforces the pathogenic model of AEBP1 mutations in Ehlers-Danlos syndrome but also informs diagnostic decision‑making and potential therapeutic targeting.

Key take‑home: The compiled genetic and functional evidence establishes a strong association between biallelic AEBP1 variants and Ehlers-Danlos syndrome, providing critical insights for precision diagnosis, patient management, and future research directions.

References

• Genes • 2019 • Expanding the Clinical and Mutational Spectrum of Recessive AEBP1-Related Classical-Like Ehlers-Danlos Syndrome PMID:30759870
• Frontiers in Genetics • 2023 • Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature PMID:37214418
• American Journal of Human Genetics • 2018 • Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome PMID:29606302
• American Journal of Medical Genetics Part A • 2019 • A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings PMID:30548383
• Biochemistry • 2005 • MAPK modulates the DNA binding of adipocyte enhancer-binding protein 1 PMID:15654748

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