The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.
Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by a partial deficiency of ferrochelatase (FECH, EC 4.99.1.1). EPP is transmitted as an autosomal dominant disorder with an incomplete penetrance. Using haplotype segregation analysis, we have identified an intronic single nucleotide polymorphism (SNP), IVS3-48T/C, that modulates the use of a constitutive aberrant acceptor splice site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism (NMD), producing a decreased steady-state level of mRNA and the additional FECH enzyme deficiency necessary for EPP phenotypic expression.
Gouya
Laurent
L
Centre Francais des Porphyries, INSERM U 409, Faculté X. Bichat, Hôpital Louis Mourier, 92701 Colombes Cedex, France.
Puy
Herve
H
Robreau
Anne-Marie
AM
Bourgeois
Monique
M
Lamoril
Jerôme
J
Da Silva
Vasco
V
Grandchamp
Bernard
B
Deybach
Jean-Charles
JC
D001483:Base Sequence; D016373:DNA, Antisense / Q000235:genetics; D005260:Female; D005294:Ferrochelatase / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D005602:France / Q000453:epidemiology; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D005799:Genes, Dominant; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D019683:Penetrance; D017354:Point Mutation; D011110:Polymorphism, Genetic; D017092:Porphyria, Erythropoietic / Q000453:epidemiology / Q000235:genetics*; D046351:Protoporphyria, Erythropoietic; D022821:RNA Splice Sites / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D016373:DNA, Antisense; D022821:RNA Splice Sites; D012333:RNA, Messenger; D005294:Ferrochelatase