ABNORMAL EXTRACELLULAR-MATRIX IN EHLERS-DANLOS SYNDROME TYPE-IV DUE TO THE SUBSTITUTION OF GLYCINE-934 BY GLUTAMIC-ACID IN THE TRIPLE-HELICAL DOMAIN OF TYPE-III COLLAGEN

A unique substitution of glycine 934 by glutamic acid in the triple he lical domain of type III collagen was identified in a proband with Ehl ers-Danlos syndrome type IV. The substitution was due to the transitio n of G 3302 to A in alpha 1(III) cDNA which is encoded by exon 46 of C OL3A1. It resulted in a severe deficiency of type III collagen in fibr oblast cultures and dermis. Dilatation of the endoplasmic reticulum of the dermal fibroblasts was probably due to the failure of these cells to secrete type III collagen molecules containing one or more mutant alpha 1(III) chains. The dermal collagen fibrils were narrow, but thei r constituent type III collagen molecules contained predominantly norm al alpha 1(III) chains. As a result, the major effect of the substitut ion of glycine 934 by glutamic acid was to severely reduce the amount of normal type III collagen available for the formation of heterotypic collagen fibrils in the extracellular matrix.