New AIP-causing HMBS genetic mutation identified in woman, 22

Mutation affected splicing, leading to low production of HMBS enzyme

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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A new mutation in the HMBS gene was identified as the cause of acute intermittent porphyria (AIP) in a 22-year-old woman in China, according to a recent study.

The mutation was found to affect splicing — the process that allows the coding regions of a gene to be joined together in different combinations — leading to the production of low amounts of the HMBS enzyme and interfering with its activity.

“These findings provide theoretical guidance for the diagnosis, treatment, and genetic counseling of AIP patients,” the researchers wrote in “Functional and structural analysis of a novel splice site HMBS variant in a Chinese AIP patient,” which was published in Frontiers in Genetics.

AIP, the most common form of acute porphyria, is caused by mutations in the HMBS gene that disrupt the activity of the hydroxymethylbilane synthase (HMBS) enzyme that’s needed for producing heme, a molecule that enables red blood cells to transport oxygen in the body.

Like other types of acute porphyria, AIP is marked by sudden and potentially severe attacks involving multiple organs that often cause abdominal pain.  The brain and other parts of the nervous system can also be affected, leading to neurological symptoms.

There are many known mutations in the HMBS gene, which can change, add, or remove genetic material in the gene and alter the enzyme’s structure or function. Some mutations affect splicing, the process by which a gene can give rise to different proteins by having its protein-coding regions (exons) joined in different combinations.

Here, researchers in China characterized a new disease-causing mutation in the HMBS gene that was found in a 22-year-old woman with AIP, who was pregnant.

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A new mutation

The woman developed severe abdominal and back pain a week before being admitted to the hospital. Three days later, she had epileptic seizures and lower limb weakness. She had a normal pregnancy and childbirth, but reported mild abdominal and back pain around menstruation.

A physical exam showed she had high blood pressure and a fast heart rate. Laboratory tests revealed low sodium levels and liver dysfunction. The AIP diagnosis was confirmed in a urine analysis, which is often used to detect high levels of porphyrin precursors.

A genetic analysis led researchers to discover a new mutation called c.648_651+1delCCAGG in exon 10 of one of the copies of the HMBS gene. The other copy was normal.

The researchers then investigated the impact of the newly discovered variant, which showed it significantly decreased HMBS production due to the degradation of its messenger RNA — a template molecule from which a protein is made — by a mechanism called nonsense-mediated mRNA decay (NMD). NMD is a quality control mechanism that targets deficient mRNA molecules for degradation.

“Our results show that the mutant protein … was significantly [shorter] than the wild type … and the expression level was significantly decreased, confirming that the variant caused a functional defect in the gene product,” the researchers wrote.

A structural analysis indicated the mutant protein completely lacked domain 3, a region that’s important for maintaining its overall stability. The mutation therefore destabilizes the HMBS protein, which “may be easily degraded and cause dose-insufficient effects,” the researchers wrote. Further functional analysis revealed the mutant had almost completely lost its enzymatic activity.

“In summary, this study first demonstrated … that the new splicing mutation (c.648_651+1delCCAGG) in the HMBS gene is pathogenic [disease causing],” wrote the researchers, who noted it also contributed to describing the “mechanism by which it causes AIP through reducing HMBS expression and activity.”