A homozygous nonsense mutation (c.214C>A) in biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis

• Published in: Journal of Medical Genetics
• Main Authors: Nytofte, Nikolaj S., Serrano, Maria A., Monte, Maria J., Tumer, Zeynep, Ladefoged, Karin, Marin, Jose J.G.
• Other Authors: Queen Ingrid's Hospital, Nuuk, Greenland, Universidad de Salamanca, Wilhelm Johannsen Centret, The Panum Institute, Copenhagen
• Format: Article in Journal/Newspaper
• Language: English
• Published: HAL CCSD 2011
• Subjects: Metabolic disorders; Gastroenterology; Liver disease; Pancreas and biliary tract; Cell biology; Greenland; inuit
• Online Access: https://hal.archives-ouvertes.fr/hal-00604039; https://hal.archives-ouvertes.fr/hal-00604039/document; https://hal.archives-ouvertes.fr/hal-00604039/file/PEER_stage2_10.1136%252Fjmg.2009.074567.pdf; https://doi.org/10.1136/jmg.2009.074567

International audience Green jaundice is a rare finding usually associated with end-stage liver diseases. We investigated two unrelated Inuit women from different geographic areas in Greenland suffering from episodes of green jaundice associated with biliary obstruction. The crises were accompanied by elevation of the biochemical markers of cholestasis, together with absent or moderate hyperbilirubinemia. In contrast, using HPLC-MS/MS hypercholanemia and high levels of biliverdin IXα in serum, urine, bile and milk were found. Hyperbiliverdinemia disappeared after surgical correction of the cholestasis. Analysis of the coding sequence of the biliverdin reductase alpha (BVRα) gene (BLVRA) detected three single nucleotide polymorphisms: c.90G>A, c.214C>A and c.743A>C, which result in p.Ala3Thr, p.Ser44X and p.Gly220Gly, respectively. Using TaqMan probes, homozigosity for c.214C>A was found in both patients. Both parents of one of these patients were heterozygous for the inactivating mutation. Her brother was homozygous for normal alleles. Although her sister was also homozygous for the c.214C>A mutation, she had suffered from neither hyperbiliverdinemia nor cholestasis. Using human liver RNA, the BVRα coding sequence was cloned and the variant containing c.214C>A was generated by site-directed mutagenesis. Both proteins were expressed in human hepatoma liver cells and oocytes. Immunobloting, immunofluorescence and functional assays of BVRα activity revealed that the mutated sequence generates a truncated protein with no catalytic activity. The present is the first report of a homozygous BLVRA inactivating mutation indicating that the complete absence of BVRα activity is a non-lethal condition, whose most evident phenotypic characteristic is the appearance of green jaundice accompanying cholestasis episodes.