Besides expanding knowledge of the molecular basis of AIP in Spain, the investigators suggest these findings also may help identify individuals who carry these mutations, but do not have any symptoms of the disease.
Their findings were described in the study, “Molecular Analysis of 55 Spanish Patients with Acute Intermittent Porphyria,” published in the journal Genes.
AIP is caused by mutations in the HMBS gene, which lower the activity of an enzyme called hepatic hydroxymethylbilane synthase (HMBS). This enzyme is required for the production of heme, a molecule essential for the transport of oxygen in red blood cells, and the breakdown of certain compounds in the liver.
In the absence of HMBS, porphyrins (heme precursors) start to build-up inside the liver and other organs, leading to the onset of AIP, including attacks of severe abdominal pain, high blood pressure, and fast heartbeat.
“Early diagnosis and counseling are essential to prevent attacks, and mutation analysis is the most accurate method to identify asymptomatic carriers in AIP families,” investigators wrote.
Scientists from the Hospital Universitario 12 de Octubre, in Madrid, analyzed the genetic mutations found in 55 unrelated patients with AIP.
All participants were diagnosed and followed at the same hospital, and experienced their first AIP attack from age 16 to 62.
The researchers collected blood samples from the patients to isolate their DNA, which they used to look for mutations in HMBS through gene-sequencing analyses.
All patients included in the study had a mutation in one of the copies of the HMBS gene. Most genetic changes were located between exons 3 and 15. (Exons are the coding regions of a gene, as they contain information to make a protein.)
The scientists identified a total of 32 HMBS mutations, including six — two deletions, two splicing defects, one insertion, and one missense mutation — never reported before, and 10 that were found in several patients.
Missense mutations are changes in only one nucleotide (the building blocks of DNA) that alter protein composition; insertions and deletions are mutations that add or remove a portion of DNA. Splicing mutations alter a DNA sequence needed for splicing, the process by which the same gene can give rise to different proteins.
When the investigators inserted the newly found missense mutation (c.294G > T) in bacteria to study its effects, they found that HMBS activity levels dropped below 1% of normal.
Additional tests also showed that the novel deletions and insertion led to the introduction of a stop codon — a sequence of three nucleotides that stops protein production — resulting in the formation of a shorter protein.
They also found that one of the new splicing mutations caused one entire exon of the HMBS gene to be lost, while the other led to the abnormal presence of one of the gene’s non-coding sequences (introns) in the resulting RNA molecule.
“These results will allow for an accurate diagnosis of carriers of the disease in these families … to provide counselling to those individuals, and to avoid precipitating factors of the disease,” the researchers wrote. “Furthermore, they increase the knowledge about the molecular heterogeneity [variability] of AIP in Spain.”
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