MOLECULAR AND CLINICAL FEATURES OF KYPHOSCOLIOTIC EHLERS-DANLOS SYNDROME DUE TO LYSYL HYDROXYLASE 1 DEFICIENCY.

Abstract

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is caused by biallelic pathogenic variants in either PLOD1, encoding the enzyme lysyl hydroxylase 1 (LH1), which is crucial for collagen lysine hydroxylation and crosslink formation or in FKBP14, encoding the collagen chaperone FKBP22. This study aims to define the clinical and molecular spectrum of kEDS-PLOD1, phenotypically compare it with kEDS-FKBP14 and explore the consequences of pathogenic PLOD1 variants on collagen biosynthesis. We studied the clinical features of 93 individuals with biallelic PLOD1 variants, including 13 unreported patients. Besides key EDS features (joint hypermobility, kyphoscoliosis, skin hyperextensibility, atrophic scarring), >70% of patients presented muscle hypotonia, and up to 26% suffered from vascular events, often at young age (perinatal intracranial hemorrhage and childhood arterial rupture). Functional studies using patient-derived skin fibroblasts revealed reduced LH1 protein levels and enzymatic activity, decreased Synaptonemal Complex 65 (SC65) levels, and reduced post-translational modifications (PTMs) in pro-α(I) collagen chains, specifically at helical crosslink-associated lysine residues. The recurrent homozygous exon 10-16 duplication generated a higher molecular weight LH1 protein with disrupted dimer organization, yet residual activity. Our findings demonstrate that disruption of the finely balanced collagen biosynthesis machinery generates collagen type-, PTM site-, and pathogenic variant-specific molecular signatures that ultimately result in the kEDS-PLOD1 phenotype, that is distinct from kEDS-FKBP14.