The HSD3B7 gene encodes the 3 beta-hydroxysteroid dehydrogenase type 7 enzyme, a member of the short-chain dehydrogenase/reductase superfamily. This enzyme is located in the membrane of the endoplasmic reticulum and plays a key role in the biosynthesis of bile acids from cholesterol. Specifically, it is responsible for catalyzing the second step in the production of bile acid, the conversion of 7alpha-hydroxycholesterol to 7α-hydroxy-4-cholesten-3-one.
Defects in the HSD3B7 affect its enzyme function and impair the bile acid biosynthesis pathway. This results in Bile Acid Synthesis Defect, Congenital, 1 (CBAS1), a neonatal-onset hepatic disorder characterized by cholestasis, jaundice, hepatomegaly and malabsorption of lipids and lipid-soluble vitamins.
The HSD3B7 gene is located on the short arm of chromosome 16. It spans a length of 4 kb of DNA and its coding sequence is spread across 7 exons. The gene encodes a 41 kDa protein product composed of 369 amino acids. An additional 21 kDa isoform of the HSD3B7 gene exists due to an alternatively spliced transcript variant. While the gene is widely expressed in the human body, overexpression is seen in the liver, testes, islets of Langerhans, adrenal gland and gallbladder. Homozygous mutations in the gene are associated with CBAS1. At least 17 HSD3B7 gene mutations have been identified in CBAS1 patients, including deletions and missense variants that hamper enzyme activity.
Monies et al. (2017) reported the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 10-year-old female from a consanguineous family, had suffered from high gamma-glutamyl transferase (GGT) cholestasis in infancy. At the time of presentation, her GGT and serum bilirubin were normal but she had elevated levels of transaminases suggestive of chronic compensated liver disease. She also had mild osteopenia, mild splenomegaly and a few gall stones. A liver biopsy indicated a diagnosis of progressive familial intrahepatic cholestasis type 3. Using a multigene panel for gastrointestinal disorders, a homozygous mutation (c.694+2T>-) was identified in exon 6 of the patient’s HSD3B7 gene, associated with congenital bile acid synthesis defect 1. Given the atypical presentation of the patient, this case helped in the phenotypic expansion of the disorder.
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