Reducible Crosslinks in Hydroxylysine-Deficient Collagens of a Heritable Disorder of Connective Tissue

Abstract

Reducible compounds that participate in crosslinking were analyzed in hydroxylysine-deficient collagens of patients with a heritable disorder of connective tissue. After treatment with [3H1sodium borohydride, new compounds, as well as a totally different pattern of tritiated compounds, were found in hydroxylysine-deficient collagen from skin as compared with age-matched controls. The amount of desmosines detected indicated that more elastin was present in abnormal skin than in control skin.Bone collagen, which was not as deficient in hydroxylysine as skin collagen, had the same compounds as normal bone collagen, but their relative proportions were altered, consistent with a deficiency of hydroxylysine, a precursor of the crosslinks. Although the content of hydroxylysine in collagen of cartilage is essentially normal in these patients, analysis after reduction revealed a different pattern of reduced compounds from that of normal cartilage. It is speculated that Type II collagen, the major collagen component in cartilage, contains a normal amount of hydroxylysine, while Type I collagen, which is the major source of the crosslinks, is hydroxylysine-deficient. This distribution would explain the findings of an abnormal profile of reducible compounds despite an almost normal total hydroxylysine content.The finding that the deficiency of hydroxylysine in the collagen of these patients is accompanied by changes in number, chemical nature, and, probably, distribution of crosslinkages, and the previously reported alterations in the solubility characteristics, suggest that at least some skeletal and connective tissue abnormalities are directly related to underlying molecular pathology.

Abnormal properties of collagen lysyl hydroxylase from skin fibroblasts of siblings with hydroxylysine-deficient collagen.

“…The skin collagen from these patients was abnormally soluble in denaturing solvents such as 4 M CaCl2 and 9 M KSCN. These observations were consistent with a deficiency of hydroxylysine-derived intermolecular cross-links, and analysis of borohydride-reducible cross-links indicated abnormalities in the nature, distribution, and amount of these moieties in the dermal collagen (2).…”

Lysyl-Protocollagen Hydroxylase Deficiency in Fibroblasts from Siblings with Hydroxylysine-Deficient Collagen

“…In normal dermal collagen, hydroxylysine constitutes about 4 residues, and lysine, about 28 per 1000 amino acids. In the affected siblings, collagen hydroxylysine content was reduced to 0.2 and 0.3 residues per 1000, respectively, while the content of lysine was not reduced, consistent with diminished hydroxylation of protocollagen lysyl residues.…”

Molecular Defects in Inborn Disorders of Collagen Metabolism

“…Other patients, clinically classified as EDS type VI and exhibiting prominent ocular symptoms, showed neither defective lysyl hydroxylase nor a lack of hydroxylysine in the skin [46]. The lack of hydroxylysine found in some patients with EDS type VI would result in abnormal cross-link forma tion of collagen fibers [47] and thus explain the weakness of connective tissue in these patients. However, differences observed in the investigated patients so far point to a great variability in the expression of the mo lecular defect and the question remains open as to whether the lack of hydroxyly sine can account for all the observed symp toms in EDS type VI.…”