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Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene.
Br J Dermatol. 2011 Sep; 165(3):499-505.BJ

Abstract

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.

Authors+Show Affiliations

Biochemistry and Molecular Genetics Department, Hospital Clinic, School of Medicine, IDIBAPS, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. JTO@clinic.ub.esNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21668429

Citation

To-Figueras, J, et al. "Hepatoerythropoietic Porphyria Due to a Novel Mutation in the Uroporphyrinogen Decarboxylase Gene." The British Journal of Dermatology, vol. 165, no. 3, 2011, pp. 499-505.
To-Figueras J, Phillips JD, Gonzalez-López JM, et al. Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. Br J Dermatol. 2011;165(3):499-505.
To-Figueras, J., Phillips, J. D., Gonzalez-López, J. M., Badenas, C., Madrigal, I., González-Romarís, E. M., Ramos, C., Aguirre, J. M., & Herrero, C. (2011). Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. The British Journal of Dermatology, 165(3), 499-505. https://doi.org/10.1111/j.1365-2133.2011.10453.x
To-Figueras J, et al. Hepatoerythropoietic Porphyria Due to a Novel Mutation in the Uroporphyrinogen Decarboxylase Gene. Br J Dermatol. 2011;165(3):499-505. PubMed PMID: 21668429.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. AU - To-Figueras,J, AU - Phillips,J D, AU - Gonzalez-López,J M, AU - Badenas,C, AU - Madrigal,I, AU - González-Romarís,E M, AU - Ramos,C, AU - Aguirre,J M, AU - Herrero,C, Y1 - 2011/08/18/ PY - 2011/6/15/entrez PY - 2011/6/15/pubmed PY - 2012/1/26/medline SP - 499 EP - 505 JF - The British journal of dermatology JO - Br. J. Dermatol. VL - 165 IS - 3 N2 - 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. SN - 1365-2133 UR - https://www.unboundmedicine.com/medline/citation/21668429/Hepatoerythropoietic_porphyria_due_to_a_novel_mutation_in_the_uroporphyrinogen_decarboxylase_gene_ L2 - https://doi.org/10.1111/j.1365-2133.2011.10453.x DB - PRIME DP - Unbound Medicine ER -