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A homozygous nonsense mutation (c.214C→A) in the biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis
  1. Nikolaj S Nytofte1,
  2. Maria A Serrano2,
  3. Maria J Monte2,
  4. Ester Gonzalez-Sanchez2,
  5. Zeynep Tumer3,
  6. Karin Ladefoged1,
  7. Oscar Briz4,
  8. Jose J G Marin2
  1. 1Queen Ingrid's Hospital, Nuuk, Greenland
  2. 2Laboratory of Experimental Hepatology and Drug Targeting, CIBERehd, University of Salamanca, Salamanca, Spain
  3. 3Kennedy Centret, Glostrup, Denmark
  4. 4Research Unit, University Hospital, CIBERehd, Salamanca, Spain
  1. Correspondence to Professor Jose J G Marin, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Campus Miguel de Unamuno E.I.D. S-09, 37007-Salamanca, Spain; jjgmarin{at}usal.es

Abstract

Background Green jaundice is a rare finding usually associated with end-stage liver disease.

Objective The authors investigated two unrelated Inuit women from different geographical areas in Greenland who had episodes of green jaundice associated with biliary obstruction.

Methods and results The crises were accompanied by increased biochemical markers of cholestasis, together with absent or moderate hyperbilirubinaemia. In contrast, high-performance liquid chromatography tandem mass spectrometry showed hypercholanaemia and high concentrations of biliverdin IXα in serum, urine, bile and milk. Hyperbiliverdinaemia 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. With the use of TaqMan probes, homozygosity 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 never had hyperbiliverdinaemia or cholestasis. With the use of 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 Xenopus laevis oocytes. Immunoblotting, immunofluorescence and functional assays of BVRα activity revealed that the mutated sequence generates a truncated protein with no catalytic activity.

Conclusion This is the first report of a homozygous BLVRA inactivating mutation indicating that the complete absence of BVRα activity is a non-lethal condition, the most evident phenotypic characteristic of which is the appearance of green jaundice accompanying cholestasis episodes.

  • Bilirubin
  • biliverdin
  • cholestasis
  • cholelithiasis
  • haem
  • liver
  • metabolic disorders
  • gastroenterology
  • liver disease
  • pancreas and biliary tract
  • cell biology

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Footnotes

  • Funding This study was supported in part by the Instituto de Salud Carlos III, FIS (Grants PI070517 and PI080151), the Junta de Castilla y Leon (Grants GR75/08, SA033A08, SA03508, and SA036A08), Spain, the Ministerio de Ciencia y Tecnología, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (Grant BFU2006-12577 and SAF2009-08493), Spain, and the Fundacion Investigacion Medica, Mutua Madrileña (Convocatoria 2009), Spain. The group is member of the Network for Cooperative Research on Membrane Transport Proteins (REIT), co-funded by the Ministerio de Educación y Ciencia, Spain and the European Regional Development Fund (ERDF) (Grant BFU2007-30688-E/BFI) and belongs to the CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas) Instituto de Salud Carlos III, Spain. Ester Gonzalez-Sanchez is a recipient of a predoctoral fellowship from the Ministerio de Educación, Spain (Grant AP2008-03762).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Human Ethics Committees of the University of Salamanca (Spain) and the Queen Ingrid's Hospital (Nuuk, Greenland).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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