Three splicing defects, an insertion, and two missense mutations responsible for acute intermittent porphyria
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Three splicing defects (IVS1+3G→T, 86A→T, IVS13–2A→G), an insertion (416insCA), and two missense mutations (664G→A and 833T→G) in the porphobilinogen deaminase (PBGD) gene were identified in six unrelated Finnish patients with acute intermittent porphyria (AIP). The IVS1+3G→T substitution resulted in activation of a cryptic splice site in intron 1 and retention of a 67-bp fragment in the mutant transcript. The 86A→T mutation at the end of exon 3 was predicted to cause an amino acid substitution (E29L). However, sequencing of the cDNA sample of the proband revealed exon 3 skipping from the mutant transcript. The IVS13–2A→G substitution caused retention of intron 13 in the mutant transcript. In exon 8, 416insCA resulted in a frameshift. All three splicing defects and the CA insertion resulted in a truncated protein and thus, probably the loss of PBGD activity. The two novel missense mutations, 664G→A in exon 12 and 833T→C in exon 14 caused a single amino acid substitution (V222M and L278P). So far 25 different mutations have been characterized from 37 (93%) of a total of 40 unrelated Finnish AIP families, confirming the genetic heterogeneity of the disease even in a previously isolated area of Finland.
KeywordsMissense Mutation Amino Acid Substitution Splice Site Genetic Heterogeneity Single Amino Acid
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