Systematic Analysis of Molecular Defects in the Ferrochelatase Gene from Patients with Erythropoietic Protoporphyria U.B. Rüfenacht, L. Gouya, X. Schneider-Yin,

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Systematic Analysis of Molecular Defects in the Ferrochelatase Gene from Patients with Erythropoietic Protoporphyria U.B. Rüfenacht, L. Gouya, X. Schneider-Yin, H. Puy, B.W. Schäfer, R. Aquaron, Y. Nordmann, E.I. Minder, J.C. Deybach The American Journal of Human Genetics Volume 62, Issue 6, Pages 1341-1352 (June 1998) DOI: 10.1086/301870 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 DGGE analysis of nine exons of the FECH gene. Lane N, Normal controls (i.e., samples with absence of either heterozygosity for mutations or polymorphisms, which appeared as a single band on the DGGE gels). Lanes P1–P26, Samples from different EPP patients with abnormal DGGE patterns (i.e., double, triple, or quadruple bands with different migration rates). The descriptions of the mutations, revealed by subsequent direct sequencing, are given in table 2. Lanes pm1–pm3, Three polymorphisms—287A/G, 798G/C, and 921A/G, respectively. Patterns from four of the positive control samples (samples with already known mutations) used in the study are presented: C1, del AA168; C2, T790C; C3, del AG970; and C4, IVS10+1, del g. The American Journal of Human Genetics 1998 62, 1341-1352DOI: (10.1086/301870) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 Agarose gel electrophoresis (ethidium bromide staining) of RT-PCR products from patients with splicing defects: exon 4 in patient P9 and exon 10 in patients P22 and P23. The sizes of PCR products are indicated. The size differences between normal cDNA fragments (upper bands) and cDNA fragments lacking the respective exon are 149 bp (exon 4 skipping) and 60 bp (exon 10 skipping). Lanes N, Normal control. Lane M, Molecular-weight markers. The American Journal of Human Genetics 1998 62, 1341-1352DOI: (10.1086/301870) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 Genomic and cDNA analyses of EPP family P10 . A, Exon 5 DGGE profile of FECH genomic DNA (mutation Y191H). B, Exon 9 DGGE profile of FECH genomic DNA (IVS8−2, a→g). C, Agarose gel electrophoresis of normal FECH cDNA fragment (599 bp) and exon 9–skipped fragment (434 bp). Lane N, Normal control. Lane MW, Molecular-weight markers. The American Journal of Human Genetics 1998 62, 1341-1352DOI: (10.1086/301870) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 4 Comparison of amino acid sequences deduced from nucleotide sequences of human (HS), mouse (MM), bovine (Bo), Saccharomyces cerevisiae (Sc), E. coli (Ec), and Bacillus subtilis (Bs). Periods (.) indicate amino acids that are identical in all FECHs; and asterisks (*) indicate amino acids that are identical in mammalian FECHs. The numbers and the boxes indicate the position of the amino acids substituted in the human sequence. The American Journal of Human Genetics 1998 62, 1341-1352DOI: (10.1086/301870) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 5 Pedigree of three EPP families with severe liver disease. A nonsense mutation (C343→T) and frameshift mutations (ins T213 and del T709) were identified in P7, P5, and P15, respectively. Among individuals who carry the mutation, overt and asymptomatic EPP patients are indicated by completely blackened and half-blackened symbols, respectively. Unblackened symbols denote normal individuals. The unblackened circle containing a question mark denotes an individual who was not tested. The clinical conditions of the EPP patients is indicated in paraphrases: photosensitivity (a), liver failure (b), liver transplantation (c), and abnormal liver-function tests (d). The American Journal of Human Genetics 1998 62, 1341-1352DOI: (10.1086/301870) Copyright © 1998 The American Society of Human Genetics Terms and Conditions