The finding adds a new layer of knowledge that may help diagnose this rare metabolic disorder and the understanding of its underlying variability.
The study, “Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria,” was published in the journal Frontiers in Pharmacology.
Acute intermittent porphyria (AIP) is a genetic disorder that is caused by mutations that impair the activity or production of hydroxymethylbilane synthase (HMBS), which is involved in the production of heme.
This disease causes recurrent acute abdominal pain that is often accompanied by gastrointestinal complications such as nausea, vomiting, and constipation. Other AIP symptoms include increased blood pressure (hypertension) and fast heart beat (tachycardia), as well as motor weakness.
“Due to the similarity to other disease symptoms, it is a challenge for clinicians to diagnose patients with intermittent porphyria at their first attack,” the researchers wrote.
To date, 421 different mutations on HMBS gene have been reported. However, for many of these mutations, their specific effects on the HMBS enzyme is unclear, as well as their potential to trigger AIP. In addition, patients with the same mutation can exhibit clinical symptoms of various severity.
Chinese researchers reviewed available information and conducted detailed analysis to better understand the role of different HMBS mutations on AIP.
The team started by collecting and reviewing all the clinical and genetic data from 117 patients available in the literature and from databases. With this information, they could revise the location of the different HMBS mutations on the enzyme’s structure and correlated these findings with the severity presented by each patient.
Next, the team used several computer algorithms to predict potential mutations that could disrupt HMBS enzyme function and cause AIP. With this approach, they identified a total of 579 missense mutations. However, a more detailed analysis, based on the prevalence reported for each of these mutations, suggested that only 34 could potentially cause AIP.
Among these 34 mutations, some were located in the same position in the structure of the enzyme as those that the team identified in the 117 patients. Some other mutations were located in specific parts of the enzyme that interact with other proteins.
“Overall, these new identified variations could be the candidates that contribute to the disease,” the researchers wrote.
Finally, the team evaluated if HMBS genetic mutations could have different frequencies among different ethnic groups.
They compared 23 previously reported missense mutations in HMBS gene among eight ethnic groups, which included South Asian, European (non-Finnish), African, East Asian, Ashkenazi Jewish, European (Finnish), Latino, and other.
The missense mutation R167W was found to be enriched in Finnish people, while the D319N variant was significantly enriched in Africans and depleted in populations from the other regions. The mutation D178N was enriched and R281H was depleted in the South Asian population compared with the global average, whereas the distribution of these two variations was the opposite in non-Finnish Europeans.
In addition, the team found that East Asian, Ashkenazi Jewish, European (Finnish), and Latino populations exhibit similar enrichment/depletion patterns, while South Asian, non-Finnish European, and African populations share overall similar distribution patterns for the 23 mutations.
“The possible explanation for these results is that the allele [one of the two gene copies we inherit] abundance may be shaped by different environmental factors and evolution patterns,” the researchers said.
Given the limited number of variations used in this analysis, the distribution pattern may not be obvious, and more studies with larger datasets are warranted to confirm these findings, they said, adding that more disease-causing variations could also provide a better view of the pattern difference among populations.