Deficiency of Galactosylhydroxylysyl Glucosyltransferase, an Enzyme of Collagen Synthesis, in a Family with Dominant Epidermolysis Bullosa Simplex

Abstract

Members of a family with dominant epidermolysis bullosa simplex were found to have a deficiency of galactosylhydroxylysyl glucosyltransferase (GGT), an enzyme catalyzing the glucosylation of galactosylhydroxylysyl residues in the biosynthesis of collagen. The enzyme's activity was low in serum, skin tissue, and cultured skin fibroblasts, although no abnormality was found in three other intracellular enzymes of collagen biosynthesis. Mixtures of serum samples from patients and healthy controls gave the expected GGT activity, indicating that the low values were not due to inhibitors. GGT deficiency was accompanied by decreased product formation in vivo, as shown by a markedly decreased urinary excretion of glucosylgalactosylhydroxylysine. Six of 12 affected members had definite GGT deficiency, and five had some evidence suggestive of this abnormality; 13 of 15 unaffected members had no such manifestations. No similar GGT deficiency was found in three other families with the same disease. We conclude that GGT deficiency may be etiologically related to this disease in some families, but that different defects must be the cause in other cases.

Reduction of Lysyl Hydroxylase 3 Causes Deleterious Changes in the Deposition and Organization of Extracellular Matrix

“…The decrease in GGT activity in a Finnish family with dominant EBS, accompanied by a markedly decreased urinary excretion of glucosylgalactosylhydroxylysine, was reported earlier (28). Among the families tested, this was the only family with a deficiency of GGT activity, indicating that this feature is unique to this family and does not represent a typical finding in EBS patients (28). In addition, Savolainen and co-workers (28) reported that the decrease in GGT activity correlated with the severity of the disease.…”

“…We have examined heterozygous LH3 knock-out mice and mouse embryonic fibroblasts (MEF ϩ/Ϫ ) at the ultrastructural level as well as cells from a human model of LH3 deficiency, an epidermolysis bullosa simplex (EBS) family member known to exhibit a decrease in GGT activity. The decrease in GGT activity in a Finnish family with dominant EBS, accompanied by a markedly decreased urinary excretion of glucosylgalactosylhydroxylysine, was reported earlier (28). Among the families tested, this was the only family with a deficiency of GGT activity, indicating that this feature is unique to this family and does not represent a typical finding in EBS patients (28).…”

“…Among the families tested, this was the only family with a deficiency of GGT activity, indicating that this feature is unique to this family and does not represent a typical finding in EBS patients (28). In addition, Savolainen and co-workers (28) reported that the decrease in GGT activity correlated with the severity of the disease. We have re-examined a patient of the EBS family and determined that the decrease in GGT activity is due to a transcriptional defect in one LH3 allele.…”

“…Fibroblast Cultures-A fibroblast culture was established from a skin biopsy specimen taken from one patient belonging to the Finnish EBS family detailed elsewhere (28). The patient marked 10 in the pedigree was re-examined in this study.…”

Lysyl Hydroxylase 3 Glucosylates Galactosylhydroxylysine Residues in Type I Collagen in Osteoblast Culture

“…The biological significance of the GGT activity of LH3 in the biosynthesis of collagen types IV and VI has been demonstrated from the studies of LH3-deficient mice (28 -30). In addition, defective GGT activity resulting from four polymorphic nucleotides in the non-coding region of Plod3 was detected in a family with dominant epidermolysis bullosa simplex (31,32). In another recent finding, two heterozygous mutations in the Plod3 coding region have been associated with a rare syndrome of congenital malformations affecting several connective tissues and organs (33).…”