AEBP1 – classical-like Ehlers-Danlos Syndrome type 2

AEBP1 encodes the adipocyte enhancer–binding protein 1/ACLP, a critical extracellular matrix component. Biallelic pathogenic variants in AEBP1 underlie classical-like Ehlers-Danlos Syndrome type 2 (clEDS2) (MONDO:0054813), an autosomal recessive connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and joint laxity.

Initial reports described six patients from consanguineous families harboring homozygous missense variant c.1925T>C (p.Leu642Pro) (PMID:30759870). A subsequent case detailed a single individual with compound heterozygous alleles c.2296G>T (p.Glu766Ter) and c.2383dup (p.Glu795GlyfsTer3) (PMID:37214418). Two siblings with homozygous frameshift c.917dup (p.Tyr306Ter) further confirmed recessive inheritance (PMID:30548383).

Segregation analyses demonstrated homozygosity of the missense allele with disease in a consanguineous pedigree and confirmed compound heterozygosity in parents of the proband. Cosegregation in two affected siblings supports pathogenicity (affected relatives = 2) (PMID:30548383).

The variant spectrum comprises one missense change (p.Leu642Pro) and three protein-truncating alleles (p.Glu766Ter, p.Glu795GlyfsTer3, p.Tyr306Ter), all predicted to undergo nonsense-mediated decay. No recurrent or founder variants have been described; allele frequencies remain extremely rare.

Functional studies in patient fibroblasts revealed irregular collagen fibril contours (“flower-like” appearance) and decreased type I/III procollagen secretion (PMID:37214418). RT-PCR in a heterozygous carrier showed monoallelic expression consistent with loss-of-function via nonsense-mediated mRNA decay (PMID:30548383).

Mechanistically, AEBP1 haploinsufficiency impairs collagen fibrillogenesis, leading to connective tissue fragility manifesting as generalized joint hypermobility (HP:0002761) and abnormal dentition (HP:0000164). Genetic testing of AEBP1 informs diagnosis, guides management, and underpins reproductive counseling in clEDS2.

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 Medical Genetics Part A • 2019 • A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings. PMID:30548383

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