Hydroxymethylbilane Synthase Gene Mutations and Polymorphisms in Brazilian Families with Acute Intermittent Porphyria

Abstract

SummaryAcute intermittent porphyria (AIP), an autosomal dominant disorder, is caused by a deficiency of hydroxymethylbilane synthase (HMBS). In the present study, we sought to establish a correlation between HMBS activity with the presence of mutations and polymorphisms. Enzyme activity was measured in red blood cells of four Brazilian unrelated AIP families (n = 124) and in blood donors (n = 80). The HMBS mutations in AIP family members were studied by PCR-SSCP followed by direct sequencing. Six intragenic SNPs (1345 G>A, 1500 T>C, 2377 C>A, 2478 A>G, 3581 A>G, and 7064 C>A) were determined by PCR-RFLP. Abnormal SSCP patterns in exons 7, 9, 12, and 15 were observed. DNA sequencing analysis revealed one nonsense mutation, R149X, two missense mutations, G111R and L338P, and one deletion, CT 730-731. All mutation carriers had lower enzyme activity. All polymorphisms, except 2377 C>A and 7064 C>A, showed no significant differences compared with previous reports. Mutation screening allowed the detection of the missense mutation, L338P, and the 730_731delCT deletion, two as yet unreported mutations in Brazilian AIP patients. Our findings also showed a high frequency of 2478 A>G and 3581 A>G polymorphism combinations suggesting that these polymorphisms contributed to enzymatic activity reduction in our study population.

Prospect and progress of gene therapy in acute intermittent porphyria

“…In the classic form of AIP, both the ubiquitous 'non-erythroid' housekeeping PBGD isoform and the 'erythroid' PBGD isoform are deficient, but only the non-erythroid isoform is directly implicated in the disease [2]. The HMBS gene spans 10 kb on chromosome 11q23 and over 370 different mutations of the gene have been described, including missense, nonsense, and splicing mutations, as well as deletions and insertions (The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff http://www.hgmd.cf.ac.uk/ac/index.php) [3][4][5]. There is no evident genotype-phenotype correlation in AIP [6].…”