Human Uroporphyrinogen-III Synthase: Genomic Organization, Alternative Promoters, and Erythroid-Specific Expression

doi:10.1006/geno.2000.6373

Genomics

Volume 70, Issue 2, 1 December 2000, Pages 223-231

https://doi.org/10.1006/geno.2000.6373 Get rights and content

Abstract

Uroporphyrinogen-III (URO) synthase is the heme biosynthetic enzyme defective in congenital erythropoietic porphyria. The ∼34-kb human URO-synthase gene (UROS) was isolated, and its organization and tissue-specific expression were determined. The gene had two promoters that generated housekeeping and erythroid-specific transcripts with unique 5′-untranslated sequences (exons 1 and 2A) followed by nine common coding exons (2B to 10). Expression arrays revealed that the housekeeping transcript was present in all tissues, while the erythroid transcript was only in erythropoietic tissues. The housekeeping promoter lacked TATA and SP1 sites, consistent with the observed low level expression in most cells, whereas the erythroid promoter contained GATA1 and NF-E2 sites for erythroid specificity. Luciferase reporter assays demonstrated that the housekeeping promoter was active in both erythroid K562 and HeLa cells, while the erythroid promoter was active only in erythroid cells and its activity was increased during hemin-induced erythroid differentiation. Thus, human URO-synthase expression is regulated during erythropoiesis by an erythroid-specific alternative promoter.

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The porphyrias are a group of inherited metabolic diseases, with each due to the deficient activity of a specific enzyme in the heme biosynthetic pathway. These are inherited as autosomal dominant, autosomal recessive, or X-linked traits, with the exception of Porphyria Cutanea Tarda, which is usually sporadic. The most common manifestations are related to the accumulation of porphyrin precursors or porphyrins, resulting in either acute neurological attacks, or cutaneous photosensitivity, or both. Multiple mutations have been identified in the genes, encoding the specific enzyme that is deficient in each of the porphyrias. Specific diagnosis criteria and treatment modalities are available for the porphyrias.
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Citation Excerpt :
The UROS gene is located on chromosome 10q26.2. The gene is ∼34 kb long and contains 10 exons, including two non-coding untranslated exons 1 and 2A, and nine coding exons 2B to 10 [20][Fig. 4]. There are two promoters, a housekeeping promoter upstream of exon 1 and an erythroid-specific promoter upstream of exon 2A, which generate housekeeping and erythroid-specific transcripts, respectively.
Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by photosensitivity and by hematologic abnormalities in affected individuals. CEP is caused by mutations in the uroporphyrinogen synthase (UROS) gene. In three reported cases, CEP has been associated with a specific X-linked GATA1 mutation. Disease-causing mutations in either gene result in absent or markedly reduced UROS enzymatic activity. This in turn leads to the accumulation of the non-physiologic and photoreactive porphyrinogens, uroporphyrinogen I and coproporphyrinogen I, which damage erythrocytes and elicit a phototoxic reaction upon light exposure.
The clinical spectrum of CEP depends on the level of residual UROS activity, which is determined by the underlying pathogenic loss-of-function UROS mutations. Disease severity ranges from non-immune hydrops fetalis in utero to late-onset disease with only mild cutaneous involvement. The clinical characteristics of CEP include exquisite photosensitivity to visible light resulting in bullous vesicular lesions which, when infected lead to progressive photomutilation of sun-exposed areas such as the face and hands. In addition, patients have erythrodontia (brownish discoloration of teeth) and can develop corneal scarring. Chronic transfusion-dependent hemolytic anemia is common and leads to bone marrow hyperplasia, which further increases porphyrin production.
Management of CEP consists of strict avoidance of exposure to visible light with sun-protective clothing, sunglasses, and car and home window filters. Adequate care of ruptured vesicles and use of topical antibiotics is indicated to prevent superinfections and osteolysis. In patients with symptomatic hemolytic anemia, frequent erythrocyte cell transfusions may be necessary to suppress hematopoiesis and decrease marrow production of the phototoxic porphyrins. In severe transfection-dependent cases, bone marrow or hematopoietic stem cell transplantation has been performed, which is curative. Therapeutic approaches including gene therapy, proteasome inhibition, and pharmacologic chaperones are under investigation.
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2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Erythropoietic Disorders Involving Heme Biosynthesis
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^☆: Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession Nos. AF230663 (housekeeping promoter sequence), AF230664 (erythroid promoter sequence), and AF230665 (erythroid cDNA).

¹: To whom correspondence should be addressed at the Department of Human Genetics, Mount Sinai School of Medicine, Fifth Avenue at 100th Street, New York, New York 10029. Telephone: (212) 659-6700. Fax: (212) 360-1809. E-mail: [email protected].

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Regular ArticleHuman Uroporphyrinogen-III Synthase: Genomic Organization, Alternative Promoters, and Erythroid-Specific Expression☆

Abstract

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Blood

Genomics

J. Biol. Chem.

Genomics

J. Biol. Chem.

J. Biol. Chem.

Genomics

Genomics

Regional assignment of the human uroporphyrinogen III synthase (UROS) gene to chromosome 10q25.2 → q26.3

Hum. Genet.

Two different genes encode delta-aminolevulinate synthase in humans: Nucleotide sequences of cDNAs for the housekeeping and erythroid genes

Nucleic Acids Res.

Genetic regulation of delta-aminolevulinate dehydratase during erythropoiesis

Nucleic Acids Res.

The gene encoding the second enzyme of the heme biosynthetic pathway, aminolevulinate dehydratase, has two transcriptional promoters

Am. J. Hum. Genet. Suppl.

Organization and expression of eucaryotic split genes coding for proteins

Annu. Rev. Biochem.

Alternative transcription and splicing of the human porphobilinogen deaminase gene result either in tissue-specific or in housekeeping expression

Proc. Natl. Acad. Sci. USA

Regular Article
Human Uroporphyrinogen-III Synthase: Genomic Organization, Alternative Promoters, and Erythroid-Specific Expression☆