Inheritance in Erythropoietic Protoporphyria: A Common Wild-Type Ferrochelatase Allelic Variant With Low Expression Accounts for Clinical Manifestation

Erythropoietic protoporphyria (EPP) is a rare autosomal dominant disorder of heme biosynthesis characterized by partial decrease in ferrochelatase (FECH; EC 4.99.1.1) activity with protoporphyrin overproduction and consequent painful skin photosensitivity and rarely liver disease. EPP is normally in...

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Bibliographic Details
Published in:Blood 1999-03, Vol.93 (6), p.2105-2110
Main Authors: Gouya, Laurent, Puy, Herve, Lamoril, Jerôme, Da Silva, Vasco, Grandchamp, Bernard, Nordmann, Yves, Deybach, Jean-Charles
Format: Article
Language:English
Subjects:
Alleles
Base Sequence
Biological and medical sciences
DNA, Complementary - analysis
DNA, Complementary - chemistry
Errors of metabolism
Female
Ferrochelatase - genetics
Gene Expression
Haplotypes
Humans
Linkage Disequilibrium
Male
Medical sciences
Metabolic diseases
Miscellaneous hereditary metabolic disorders
Mutation
Pedigree
Porphyria, Hepatoerythropoietic - genetics
Protoporphyria, Erythropoietic
RNA, Messenger - analysis
Sequence Analysis, DNA
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Summary:Erythropoietic protoporphyria (EPP) is a rare autosomal dominant disorder of heme biosynthesis characterized by partial decrease in ferrochelatase (FECH; EC 4.99.1.1) activity with protoporphyrin overproduction and consequent painful skin photosensitivity and rarely liver disease. EPP is normally inherited in an autosomal dominant pattern with low clinical penetrance; the many different mutations that have been identified are restricted to one FECH allele, with the other one being free of any mutations. However, clinical manifestations of dominant EPP cannot be simply a matter ofFECH haploinsufficiency, because patients have enzyme levels that are lower than the expected 50%. From RNA analysis in one family with dominant EPP, we recently suggested that clinical expression required coinheritance of a normal FECH allele with low expression and a mutant FECH allele. We now show that (1) coinheritance of a FECH gene defect and a wild-type low-expressed allele is generally involved in the clinical expression of EPP; (2) the low-expressed allelic variant was strongly associated with a partial 5′ haplotype [−251G IVS1−23T IVS2μsatA9] that may be ancestral and was present in an estimated 10% of a control group of Caucasian origin; and (3) haplotyping allows the absolute risk of developing the disease to be predicted for those inheriting FECH EPP mutations. EPP may thus be considered as an inherited disorder that does not strictly follow recessive or dominant rules. It may represent a model for phenotype modulation by mild variation in expression of the wild-type allele in autosomal dominant diseases.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V93.6.2105.406k28_2105_2110