Funding sources Supported by Spanish ‘Fondo de Investigación Sanitaria’ (FIS PI06/0150) and NIH Funding NIDDK DK020503 to J.D. Phillips.
CLINICAL AND LABORATORY INVESTIGATIONS
Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene
Article first published online: 18 AUG 2011
© 2011 The Authors. BJD © 2011 British Association of Dermatologists
British Journal of Dermatology
Volume 165, Issue 3, pages 499–505, September 2011
How to Cite
To-Figueras, J., Phillips, J.D., Gonzalez-López, J.M., Badenas, C., Madrigal, I., González-Romarís, E.M., Ramos, C., Aguirre, J.M. and Herrero, C. (2011), Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. British Journal of Dermatology, 165: 499–505. doi: 10.1111/j.1365-2133.2011.10453.x
Conflicts of interest None declared.
- Issue published online: 28 AUG 2011
- Article first published online: 18 AUG 2011
- Accepted manuscript online: 11 JUN 2011 10:30AM EST
- Accepted for publication 22 May 2011
Background Hepatoerythropoietic porphyria (HEP) is a rare form of porphyria that results from a deficiency of uroporphyrinogen decarboxylase (UROD). The disease is caused by homoallelism or heteroallelism for mutations in the UROD gene.
Objective To study a 19-year-old woman from Equatorial Guinea, one of the few cases of HEP of African descent and to characterize a new mutation causing HEP.
Methods Excretion of porphyrins and residual UROD activity in erythrocytes were measured and compared with those of other patients with HEP. The UROD gene of the proband was sequenced and a new mutation identified. The recombinant UROD protein was purified and assayed for enzymatic activity. The change of amino acid mapped to the UROD protein and the functional consequences were predicted.
Results The patient presented a novel homozygous G170D missense mutation. Porphyrin excretion showed an atypical pattern in stool with a high pentaporphyrin III to isocoproporphyrin ratio. Erythrocyte UROD activity was 42% of normal and higher than the activity found in patients with HEP with a G281E mutation. The recombinant UROD protein showed a relative activity of 17% and 60% of wild-type to uroporphyrinogen I and III respectively. Molecular modelling showed that glycine 170 is located on the dimer interface of UROD, in a loop containing residues 167–172 that are critical for optimal enzymatic activity and that the carboxyl side chain from aspartic acid is predicted to cause negative interactions between the protein and the substrate.
Conclusions The results emphasize the complex relationship between the genetic defects and the biochemical phenotype in homozygous porphyria.