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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 2105-2110
Inheritance in Erythropoietic Protoporphyria: A Common Wild-Type
Ferrochelatase Allelic Variant With Low Expression Accounts for
Clinical Manifestation
Laurent Gouya,
Herve Puy,
Jerôme Lamoril,
Vasco Da Silva,
Bernard Grandchamp,
Yves Nordmann, and
Jean-Charles Deybach
From the Centre Francais des Porphyries, INSERM U 409, Faculté
X. Bichat, Hôpital Louis Mourier, Colombes, France.
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 of
FECH 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 IVS123T
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.
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