Three splicing defects, an insertion, and two missense mutations responsible for acute intermittent porphyria

• Published in: Human genetics 1998-05, Vol.102 (5), p.541-548
• Main Authors: MUSTAJOKI, S, PIHLAJA, H, AHOLA, H, PETERSEN, N. E, MUSTAJOKI, P, KAUPPINEN, R
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; DNA Mutational Analysis; Errors of metabolism; Humans; Hydroxymethylbilane Synthase - genetics; Medical sciences; Metabolic diseases; Mutation; Porphyria, Acute Intermittent - genetics; Proteins and glycoproteins
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s004390050737

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.