Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX, USA.
Mol Genet Metab. 2019 Nov;128(3):363-366. doi: 10.1016/j.ymgme.2018.11.013. Epub 2018 Nov 28.
Porphyria Cutanea Tarda (PCT) is a cutaneous porphyria that results from the hepatic inhibition of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD), and can occur either in the absence or presence of an inherited heterozygous UROD mutation (PCT subtypes 1 and 2, respectively). A heterozygous UROD mutation causes half-normal levels of UROD activity systemically, which is a susceptibility factor but is not sufficient alone to cause type 2 PCT. In both Types 1 and 2 PCT, the cutaneous manifestations are precipitated by additional factors that lead to generation of an inhibitor that more profoundly reduces hepatic UROD activity. PCT is an iron-related disorder, and many of its known susceptibility factors, which include infections (e.g. hepatitis C virus, HIV), high alcohol consumption, smoking, estrogens, and genetic traits (e.g. hemochromatosis mutations) can increase hepatic iron accumulation. Hepatoerythropoietic Porphyria (HEP) is a rare autosomal recessive disease that results from homozygosity or compound heterozygosity for UROD mutations and often causes infantile or childhood onset of both erythropoietic and cutaneous manifestations. During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for 387 unrelated patients with PCT and four unrelated patients with HEP. Of the 387 unrelated individuals tested for Type 2 PCT, 79 (20%) were heterozygous for UROD mutations. Among 26 family members of mutation-positive PCT patients, eight (31%) had the respective family mutation. Additionally, of the four unrelated HEP patients referred for UROD mutation analyses, all had homozygosity or compound heterozygosity for UROD mutations, and all eight asymptomatic family members were heterozygotes for UROD mutations. Of the UROD mutations identified, 19 were novel, including nine missense, two nonsense, one consensus splice-site, and seven insertions and deletions. These results expand the molecular heterogeneity of PCT and HEP by adding a total of 19 novel UROD mutations. Moreover, the results document the usefulness of molecular testing to confirm a genetic susceptibility trait in Type 2 PCT, confirm a diagnosis in HEP, and identify heterozygous family members.
迟发性皮肤卟啉病（PCT）是一种皮肤卟啉病，是由于肝内尿卟啉原脱羧酶（UROD）的血红素生物合成酶抑制引起的，可发生于遗传性杂合 UROD 突变（分别为 PCT 亚型 1 和 2）缺失或存在的情况下。杂合 UROD 突变导致全身 UROD 活性水平降低一半，这是一个易感因素，但单独不足以引起 2 型 PCT。在 1 型和 2 型 PCT 中，皮肤表现均由导致肝 UROD 活性更严重降低的抑制剂产生的其他因素引发。PCT 是一种与铁相关的疾病，其许多已知的易感因素包括感染（例如丙型肝炎病毒、HIV）、大量饮酒、吸烟、雌激素和遗传特征（例如血色病突变），这些因素会增加肝铁的积累。肝红细胞生成性卟啉病（HEP）是一种罕见的常染色体隐性疾病，由 UROD 突变的纯合子或复合杂合子引起，常导致红细胞生成和皮肤表现的婴儿期或儿童期发病。在 2007 年 1 月 1 日至 2017 年 12 月 31 日的 11 年期间，西奈山卟啉症诊断实验室为 387 名无关的 PCT 患者和 4 名无关的 HEP 患者提供了分子诊断检测。在 387 名接受 2 型 PCT 检测的无关个体中，79 名（20%）为 UROD 突变的杂合子。在 26 名突变阳性 PCT 患者的家族成员中，有 8 名（31%）有各自的家族突变。此外，在转介进行 UROD 突变分析的 4 名无关 HEP 患者中，所有人均为 UROD 突变的纯合子或复合杂合子，所有 8 名无症状的家族成员均为 UROD 突变的杂合子。在所鉴定的 UROD 突变中，有 19 个是新的，包括 9 个错义突变、2 个无义突变、1 个共识剪接位点和 7 个插入和缺失。这些结果通过增加总共 19 个新的 UROD 突变，扩展了 PCT 和 HEP 的分子异质性。此外，这些结果证明了分子检测在确认 2 型 PCT 的遗传易感性特征、确认 HEP 的诊断以及识别杂合子家族成员方面的有用性。
