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

Human Genetics
S MustajokiRaili Kauppinen

Abstract

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.

Citations

Oct 25, 2003·Nucleic Acids Research·Xavier RocaAdrian R Krainer
Jun 12, 2001·Genetics in Medicine : Official Journal of the American College of Medical Genetics·R B RamdallR J Desnick
Nov 10, 2001·Annual Review of Genomics and Human Genetics·J Kere
Feb 24, 2001·Scandinavian Journal of Clinical and Laboratory Investigation·P E JørgensenA Brock
Jan 30, 2002·Blood Cells, Molecules & Diseases·Maria Domenica CappelliniGemino Fiorelli
Apr 23, 2002·Nature Reviews. Genetics·Luca CartegniAdrian R Krainer
Dec 16, 2000·Journal of Inherited Metabolic Disease·U GrossM O Doss
Jan 7, 2000·The American Journal of Medicine·S E Mattern, A Tefferi

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