LACK OF 3-BETA-HYDROXY-DELTA-5-C-27-STEROID DEHYDROGENASE ISOMERASE IN FIBROBLASTS FROM A CHILD WITH URINARY-EXCRETION OF 3-BETA-HYDROXY-DELTA-5-C-27-BILE ACIDS - A NEW INBORN ERROR OF METABOLISM

Cultured fibroblasts were shown to be capable of catalyzing the conversion of 7α-hydroxy-cholesterol to 7α-hydroxy-4-cholesten-3-one, an important reaction in bile acid synthesis. The apparent K(m) was ~7 μmol/liter and V(max) varied between 3 and 9 nmol/mg protein per 1 h under the assay conditions used. The assay was used to investigate fibroblasts from a patient who presented with a familial giant cell hepatitis and who was found to excrete the monosulfates of 3β,7α-dihydroxy-5-cholenoic acid and 3β,7α,12α-trihydroxy-5-cholenoic acid in urine (Clayton, P.T., J.V. Leonard, A.M. Lawson, K.D.R. Setchell, S. Andersson, B. Egestad, and J. Sjovall. 1987. J. Clin. Invest. 79:1031-1038). In addition 7α-hydroxy-cholesterol was found to accumulate in the circulation. Cultured fibroblasts from this boy were completely devoid of 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase activity. Fibroblasts from his parents had reduced activity, compatible with a heterozygous phenotype. The results provide strong evidence for the suggestion that this patient's liver disease was caused by a primary defect in the 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase involved in bile acid biosynthesis.