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December 1999 • Volume 30 • Number 6


Correspondence
 Extremely Rare Association of HFE Mutations With Porphyria Cutanea Tarda in Japanese Patients

Kazumichi Furuyama1,2 [MEDLINE LOOKUP]
Masao Kondo3 [MEDLINE LOOKUP]
Kenji Hirata4 [MEDLINE LOOKUP]
Hiroyoshi Fujita4 [MEDLINE LOOKUP]
Shigeru Sassa2 [MEDLINE LOOKUP]

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Porphyria cutanea tarda (PCT) is caused by decreased activity of hepatic uroporphyrinogen decarboxylase. The disease is characterized clinically by photosensitive skin lesions, and biochemically by accumulation and excretion of uroporphyrin into urine and isocoproporphyrin into feces.1 Excess hepatic iron, together with inappropriately high iron absorption, also occurs in PCT. HLA-H (now termed HFE) has recently been reported to be a candidate gene for hereditary hemochromatosis (HH) on the short arm of chromosome 6, as 2 separate mutations have been found in HH patients and in patients with PCT. Eighty-seven percent of HH patients have a G to A transition at nucleotide 845 of the open reading frame of HFE that results in a cysteine to tyrosine substitution at amino acid 282 (C282Y).2 The second missense mutation, H63D, was caused by a C to G transversion at 187 nucleotides of the open reading frame. A role for genetic hemochromatosis in the pathogenesis of iron overload in PCT has been also suggested,3 and high association of HFE and PCT has been reported in Italian4 as well as in British patients.5

Although HH is common in populations of Northern European origin, with frequency of 1 of 200 to 1 of 300,6 it is rare in African, Asian, and Australian populations.6 We studied the occurrence of the 2 HFE mutations (C282Y and H63D) in Japanese patients with PCT. A total of 20 cases of PCT (17 men, and 3 women; age ranging from 28 to 67 years of age) were studied, which were well documented by the characteristic skin photosensitivity, elevated urinary porphyrin concentrations, and fecal isocoproporphyrin.

Genomic DNA was extracted from peripheral blood mononuclear cells. Using polymerase chain reaction, the fourth plus the fifth exon with the fourth intron, and the second plus the third exon with the second intron of the HFE gene, were amplified using primers, 5´-ATCCCTCTCCTCATCCTTCCT-3´, 5´-AGAGACTTCCCCCTTGTTCCTACT-3´, and 5´-ATGGTTAAGGCCTGTTGCTCTGTCTC-3´, 5´-CAACCTCCTCCACTCTGCCACTA-3´, respectively. C282Y mutation was identified by restriction fragment length polymorphism (RFLP) analysis using SnaBI, whereas H63D mutation was identified by RFLP analysis using BclI. The results of our study showed that there were no C282Y mutations, whereas there was 1 H63D mutation among 40 chromosomes from Japanese patients with PCT. This finding suggests that HFE gene mutations are extremely rare in Japanese patients with PCT, and it is consistent with the recent report that the C282Y mutation was not found in 504 chromosomes from 252 unrelated healthy Japanese, and the H63D mutation was found at only 0.99% frequency.7 It is likely that abnormal iron metabolism associated with PCT in Japanese patients occurs by a mechanism unrelated to HFE gene mutations, and the pursuit of such a question may lead to the identification of a non-HFE–mediated iron overloading mechanism.
Acknowledgment

The authors thank Luba Garbaczewski and Sakiko Kusunoki for their technical assistance in this work. This work was supported in part by grants from United States Public Health Service grant DK32890 (to S.S.), Ya-manouchi Molecular Medicine Fund (to K.F.), and Chugai Fund for Molecular Hematology (to S.S.).


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