New gene mutation ID’d as cause of family’s hereditary angioedema
Nearly all HAE cases are caused by mutations in SERPING1 gene
A new mutation in the SERPING1 gene was identified as the cause of hereditary angioedema (HAE) in several members of a Han Chinese family, a study reports.
Blood tests revealed varied levels of C1-INH, the protein encoded by the SERPING1 gene and used to help diagnose the condition, in affected and unaffected family members. The findings indicate it’s “difficult to accurately diagnose HAE based solely on the levels of C1-INH,” the researchers wrote.
The study, “Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema,” was published in the Orphanet Journal of Rare Diseases.
Nearly all cases of HAE are caused by mutations in the SERPING1 gene, which disrupt C1-INH’s production or function. Because the protein helps regulate the levels of bradykinin, a pro-inflammatory signaling molecule, a lack of working C1-INH can lead to the sudden swelling attacks characteristic of HAE.
“The gradual decline in C1-INH secretion over a prolonged period, ultimately leads to the manifestation of HAE disease,” wrote the researchers, who said studying the effects of SERPING1 mutations in C1-INH “may also be one of the best entry points for exploring the occurrence of HAE.”
A new SERPING1 mutation
Here, researchers describe the identification of a previously unknown SERPING1 mutation called c.708T>G as the cause of HAE in five members of a Han Chinese family.
The first family member diagnosed with HAE was a 71-year-old woman. Also diagnosed were her 32-year-old daughter, her 60-year-old sister, a 63-year-old brother, and a cousin, 64. Eight unaffected family members were also studied. In all the affected members, the mutation was detected in only one of the two gene copies.
The researchers then conducted analyses to determine the effects of the mutation and found the variant likely destabilizes the C1-INH protein, affecting its function.
Experiments in lab-grown human cells showed the variant led to C1-INH clumps being formed in the endoplasmic reticulum, a network of flattened sacs within cells where proteins mature. This resulted in a decrease in C1-INH secretion and triggered the increased production of a protein called GRP75 and a marked increase in calcium levels. The excess calcium disrupted the structure and function of mitochondria, the so-called powerhouses of cells, leading to their death.
The effects were similar to those reported about a known SERPING1 mutation called c.550G>A, further supporting the involvement of GRP75 and calcium in HAE. Experiments to reduce GRP75 production mitigated the calcium overload and mitochondrial damage induced by the SERPING1 mutation.
“Based on our findings, we propose that the detection of [calcium levels within cells] could serve as a valuable biomarker for predicting acute attacks of HAE in patients,” the researchers wrote.
Unreliability of C1-INH levels in making a diagnosis
Blood samples from all 13 family members were collected to measure levels of C1-INH and C4, a protein broken down by an enzyme normally blocked by C1-INH. The affected family members were expected to have low levels of C1-INH and C4.
Among the members with HAE, the woman and her daughter had higher than normal C1-INH levels, but her younger brother and cousin had levels below the normal range, and her sister had normal levels. Most of the unaffected family members had C1-INH in the normal range, except for another sister and a granddaughter who had levels that were higher than normal.
The woman and her cousin fell within the normal range for C4, while her sister, younger brother, and daughter showed higher levels. Normal C4 levels were detected in most of the unaffected members, except for the woman’s sister and another brother, whose were higher.
“The [blood] C1-INH and C4 levels in some patients … were not lower than those of normal subjects,” the researchers wrote.
The fact that samples from patients weren’t collected during an acute swelling attack and the significant differences between family members regarding age, sex, lifestyle, medication, and other chronic inflammatory diseases may explain the discrepancies in these results, the researchers surmised.
“Based on our findings and previous literature, we can conclude that the assessment of HAE status based on peripheral blood C1-INH and C4 levels is not entirely reliable,,” and HAE patients may be mistakenly perceived “as ‘normal,’ ultimately leading to a missed diagnosis or delayed diagnosis,” they wrote.
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