An Ehlers-Danlos syndrome type VIA patient with cystic malformations of the meninges.

We have characterized a patient with the phenotype of Ehlers-Danlos syndrome type VIA (EDS VIA: kyphoscoliotic form), accompanied by the unique feature of cystic malformations of the meninges, to be homozygous for a large duplication of 8.9 kb in the lysyl hydroxylase 1 (LH1) gene that is the cause of severely decreased levels of LH activity in her skin fibroblasts. Electrophoresis of full length cDNA for LH1, prepared from the patient's fibroblasts and amplified by PCR, showed an abnormally large DNA fragment indicative of a duplication mutation; this mutation was confirmed in genomic DNA by PCR using duplication-specific primers and sequence analysis of the duplication junction. The homozygosity of this mutation was confirmed by analysis of DNA from the unaffected parents which showed them to be carriers of this duplication. This seven exon duplication is the most common mutation in the LH1 gene in patients with EDS VIA and occurs via a homologous recombination of Alu sequences in introns 9 and 16. Using the data from this study and other recent reports, we have updated the allele frequency for this mutation, based on 19 duplicated alleles out of a total of 104 genetically independent alleles from 53 EDS VIA families, to be 18.3%.

Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing.

Patients with OI/EDS form a distinct subset of osteogenesis imperfecta (OI) patients. In addition to skeletal fragility, they have characteristics of Ehlers-Danlos syndrome (EDS). We identified 7 children with types III or IV OI, plus severe large and small joint laxity and early progressive scoliosis. In each child with OI/EDS, we identified a mutation in the first 90 residues of the helical region of alpha1(I) collagen. These mutations prevent or delay removal of the procollagen N-propeptide by purified N-proteinase (ADAMTS-2) in vitro and in pericellular assays. The mutant pN-collagen which results is efficiently incorporated into matrix by cultured fibroblasts and osteoblasts and is prominently present in newly incorporated and immaturely cross-linked collagen. Dermal collagen fibrils have significantly reduced cross-sectional diameters, corroborating incorporation of pN-collagen into fibrils in vivo. Differential scanning calorimetry revealed that these mutant collagens are less stable than the corresponding procollagens, which is not seen with other type I collagen helical mutations. These mutations disrupt a distinct folding region of high thermal stability in the first 90 residues at the amino end of type I collagen and alter the secondary structure of the adjacent N-proteinase cleavage site. Thus, these OI/EDS collagen mutations are directly responsible for the bone fragility of OI and indirectly responsible for EDS symptoms, by interference with N-propeptide removal.