Heterogeneous basis of the type VIB form of Ehlers–Danlos syndrome (EDS VIB) that is unrelated to decreased collagen lysyl hydroxylation

Abstract

Skin fibroblasts from the majority of patients with the clinical diagnosis of Ehlers-Danlos syndrome type VI (EDS VI; kyphoscoliosis type), have significantly decreased lysyl hydroxylase (LH) activity due to mutations in the LH1 gene (classified as EDS VIA: OMIM no. 225400). A rare condition exists in which patients are clinically similar but have normal levels of LH activity (designated EDS VIB: OMIM no. 229200). To define the biochemical defect, we have examined cultured fibroblasts from four EDS VIB patients for changes in the levels of the mRNAs for LH1, LH2, and LH3, collagen cross-linking patterns, and the extent of lysine hydroxylation of type I collagen alpha chains. Although normal levels of LH1 mRNA were observed in all four patients, in two patients the levels of LH2 mRNA were decreased by >50%, and a similar decrease was observed in LH3 mRNA in the other two patients. A distinct pattern of collagen cross-links, indicative of decreased lysyl hydroxylation, could be identified in EDS VIA patients, but there was no clear correlation between collagen cross-link pattern and changes in the individual LH mRNAs in EDS VIB patients. Linkage to tenascin-X was excluded in these patients. This study suggests that the basis for this form of EDS VI is genetically heterogeneous, and that alternative pathways in addition to lysine hydroxylation of collagen may be affected.

Tissue-specific expression and regulation of the alternatively-spliced forms of lysyl hydroxylase 2 (LH2) in human kidney cells and skin fibroblasts

“…Their clinical phenotype results from a deficiency of LH caused by several different mutations in the LH1 gene (Yeowell and Walker, 2000), also named procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD). A rarer condition exists in which patients are clinically similar but have normal levels of LH activity (EDSVIB: OMIM# 229200; Walker et al, 2004). Two other enzymes with LH activity and a high overall identity with LH1, designated LH2 and the alternatively spliced form LH2alt (Yeowell and Walker, 1999), and LH3 (Valtavaara et al, 1998;Passoja et al, 1998), have since been characterized.…”

A Novel Mutation in the Lysyl Hydroxylase 1 Gene Causes Decreased Lysyl Hydroxylase Activity in an Ehlers–Danlos VIA Patient

“…Analysis of cross-linking in long-term fibroblast cultures Reducible bi-functional collagen cross-links were measured in longterm cultures of patients's fibroblast cell lines as previously described (Walker et al, 2004a).…”

“…A second, rarer form of EDS VI has been described, EDS VIB (OMIM no. 229200), in which patients have the clinical phenotype of EDS VI but with normal levels of LH activity (Walker et al, 2004a).…”

Atypical Symptom of Ehlers-Danlos Syndrome Impeding Diagnosis: Feeling of Spinal Instability

“…Ehlers-Danlos syndrome (EDS) has a genetic background and is caused by defects in collagen biosynthesis 1 . The main features of EDS are hyperelasticity, fragility of skin, hyperlaxity of the joints, and bleeding diathesis 2,3 .…”