Study Identifies 40 New Mutations That Cause Acute Intermittent Porphyria

Forty previously unreported mutations in the HMBS gene have been identified and found to be associated with the development of acute intermittent porphyria.

Researchers at the Icahn School of Medicine at Mount Sinai, New York, described the mutations in the study “Identification and characterization of 40 novel hydroxymethylbilane synthase mutations that cause acute intermittent porphyria,” which was published in the Journal of Inherited Metabolic Disease.

Acute intermittent porphyria (AIP) is the most common of the four types of acute porphyrias. It is caused by mutations in the gene that provides instruction to make the hydroxymethylbilane synthase, or HMBS, enzyme. These mutations often make the enzyme unable to carry out its normal function of helping to make heme, a molecule that helps red blood cells carry oxygen.

More than 90% of people with AIP are asymptomatic, meaning they never show signs of the disease. However, some patients may experience acute attacks that characterize the disease, which can result in abdominal pain, constipation, seizures, muscle weakness, high blood pressure, and elevated heart rate.

Genetic testing is crucial for diagnosis. Not only can this identify the problem in people with symptoms, it can allow asymptomatic individuals to be aware of the risks and the chance they will pass the mutated gene to their children.

To date, more than 400 AIP-causing mutations have been identified. In this new study, researchers report on 40 more.

The mutations were found in 43 unrelated individuals who, after experiencing symptoms typical of AIP, had blood samples taken and had porphyria-related genes analyzed.

Most (28) of the mutations were predicted to severely impact the protein, changing its DNA sequence in such a way that the whole gene could not be properly read. These changes included premature stop signals (nonsense mutations), insertions and deletions that cause a frameshift of the sequence, and mutations that change how the gene is spliced (rearranged for making the protein).

Eleven mutations were missense, meaning they changed only one amino acid in the protein produced. There also was one deletion that did not cause a frameshift. The researchers used molecular tests to characterize these variants a little further, since the mechanism by which they prevent the protein from working was not fully clear.

HMBS proteins carrying each one of these mutations, with the exception of one mutation, were found to have significantly reduced activity — about less than 5% that of the non-mutated HMBS version. The exception, a mutation identified as p.A347P, had about half the activity of the non-mutated protein, but further tests revealed this mutation made the protein less stable.

Further characterization of these proteins revealed that the way they “broke” the protein depended on where the mutation appeared in the three-dimensional structure of the protein.

Specifically, mutations that changed the active pocket of HMBS — the portion responsible for doing the enzyme’s job — prevented it from working by directly changing it. In contrast, mutations on the outside of the protein appeared to reduce the activity of HMBS by making it less stable so that it  degraded rapidly.

“These studies facilitated the molecular diagnoses of AIP family members and further expanded the molecular heterogeneity of this acute hepatic porphyria,” researchers wrote.