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Molecular Genetics of 3ß-Hydroxy-⁵-C₂₇-Steroid Oxidoreductase Deficiency in 16 Patients with Loss of Bile Acid Synthesis and Liver Disease

Department of Molecular Genetics (J.B.C., D.W.R.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046; Department of Biochemistry (M.G.), St. Joseph Hospital, 75674 Paris, France; Pediatric Hepatology and Inserm U347 (E.J., D.C.), Bicêtre University Hospital and Public Assistance Hospital of Paris, 94275 Paris, France; Department of Pediatrics (H.N.), King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia 11211; and Department of Pediatrics (J.E.H., K.D.R.S.), Cincinnati Children’s Hospital, Cincinnati, Ohio 45229

Address all correspondence and requests for reprints to: Dr. David W. Russell, Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9046. E-mail: david.russell{at}utsouthwestern.edu.

The 3ß-hydroxy-⁵-C₂₇-steroid oxidoreductase (C₂₇ 3ß-HSD) is a membrane-bound enzyme of the endoplasmic reticulum that catalyzes an early step in the synthesis of bile acids from cholesterol. Subjects with autosomal recessive mutations in the encoding gene, HSD3B7, on chromosome 16p11.2–12 fail to synthesize bile acids and develop a form of progressive liver disease characterized by cholestatic jaundice and malabsorption of lipids and lipid-soluble vitamins from the gastrointestinal tract. The gene encoding the human C₂₇ 3ß-HSD enzyme was isolated previously, and a 2-bp deletion in exon 6 of HSD3B7 was identified in a well characterized subject with this disorder. Here, we report a molecular analysis of 15 additional patients from 13 kindreds with C₂₇ 3ß-HSD deficiency. Twelve different mutations were identified in the HSD3B7 gene on chromosome 16p11.2–12. Ten mutations were studied in detail and shown to cause complete loss of enzyme activity and, in two cases, alterations in the size or amount of the transcribed mRNA. Mutations were inherited in homozygous form in 13 subjects from 10 families and compound heterozygous form in four subjects from three families. We conclude that a diverse spectrum of mutations in the HSD3B7 gene underlies this rare form of neonatal cholestasis.

This work was supported by grants from the NIH (HL-20948, to D.W.R.), the Assistance Publique-Hospitaux de Paris (PHRC AOB 96026, to E. J.), and the NIH National Center for Research Resources (M0108084, to the Cincinnati Children’s Hospital General Clinical Research Center).

Abbreviations: 25-Hydroxycholesterol, [³H]cholest-5-ene-3ß,25-diol; C₂₇ 3ß-HSD, 3ß-hydroxy-⁵-C₂₇-steroid oxidoreductase; HEK, human embryonic kidney; OMIM, Online Mendelian Inheritance of Man.

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