The case report, “The first Japanese case of familial porphyria cutanea tarda diagnosed by a UROD mutation,” appeared in the Journal of Dermatological Science.
PCT, the most frequent type of porphyria, is characterized by skin sensitive to light, blistering on the face and hands, and liver damage. Its familial form, or type II, is caused by a heterozygous mutation (in one of the gene copies) in UROD.
The team from Hirosaki University Graduate School of Medicine, in Japan, presented the first case of familial PCT in the country with genetic analysis. According to the researchers, genetic testing was not conducted in the previous four PCT cases with positive family histories in Japan.
A 26-year old fisherman presented with a four-year history of exanthema (skin rash) after sun exposure. He had been diagnosed with liver damage two months before presentation. Excessive alcohol consumption — a known trigger of familial PCT — had started around age 15. He had no family history of PCT.
Physical examinations found several fine pitted scars across the face and diffuse erythema (redness), particularly on the upper eyelid. The man’s hands had patches of various sizes with crusting and pigmentation.
He had elevated levels of aspartate transaminase (AST), alanine transaminase (ALT), and gamma-glutamyltransferase (γ-GTP), all indicators of liver damage. The patient had greatly increased urine uroporphyrin levels (604 mg/dL, normal range is under 36 mg/dL), prompting a diagnosis of PCT.
The team subsequently conducted genetic testing, using DNA extracted from peripheral blood leukocytes (white blood cells) of the patient, his older brother, and his parents. This revealed a heterozygous single nucleotide change — an alteration in only one of the DNA building blocks — in the patient, specifically at the border between intron 6 and exon 7 of UROD, designated as c.673-2A>C. Of note, while exons are the DNA bits containing the information to make proteins, introns are normally spliced out during gene expression (protein production).
The location of the nucleotide change suggested that exon skipping, which occurs when the cellular machinery skips over specific exons in gene expression, was possible. In agreement, molecular analysis revealed that both shortened messenger RNA (mRNA, generated from DNA) missing exon 7 and full-length mRNA were produced.
Then, the investigators observed that this mutation reduced the level of normal UROD protein to about half and led to the production of a shorter-than-expected protein, likely the result of instability and increased degradation, they suggested.
Overall, the team highlighted that this mutation not only had not been previously reported, but also that it is a de novo change, meaning alterations that occur during embryonic development and not inherited from parents.
The patient’s light sensitivity and liver damage were eased with sun protection and abstinence. As such, “efforts to detect UROD mutation heterozygotes in PCT families are required to prevent these individuals from developing PCT by encouraging them to avoid known precipitating factors,” the investigators said.