A newly identified gain-of-function mutation in the STAT1 gene was associated with the development of bronchiectasis in a 17-year-old boy with a long history of persistent infections in the mouth and lungs.
This case adds to previous studies reporting similar links between STAT1 gain-of-function mutations and bronchiectasis, supporting evidence that such mutations may increase the risk of developing the chronic airway condition.
The patient also had high levels of a specific antibody called IgA, the clinicians found.
Gain-of-function mutations are those that result in a protein with higher-than-normal activity. Antibodies, or immunoglobulins (Igs), are protective proteins produced by immune B-cells against a particular foreign molecule or microbe found in the body.
Clinicians should consider the presence of STAT1 gain-of-function mutations in people with unexplained chronic canker sores, bacterial lung infections, bronchiectasis, and an increase in IgA levels, the researchers said.
The case report, “Chronic Candida infection, bronchiectasis, immunoglobulin abnormalities, and stunting: a case report of a natural mutation of STAT1 (c.986C>G) in an adolescent male,” was conducted by scientists at Zhongnan Hospital, in Wuhan City, China. It was published in the journal BMC Infectious Diseases.
Bronchiectasis is characterized by an irreversible expansion, inflammation, and scarring of the bronchi, the small airways of the lungs. It may be caused by repeat bacterial infections, allergies, and autoimmune diseases, in which the immune system mistakenly attacks the body’s own molecules.
The condition also may be associated with genetic diseases that affect mucus production in the lungs or impair immune responses — including those causing IgA deficiency.
Mutations in the STAT1 gene are known to affect a number of immune responses, “thereby affecting host immune defence capacity and increasing susceptibility to mycobacteria, fungi and viruses,” the researchers wrote.
Gain-of-function mutations in this gene are associated with diverse clinical manifestations, including chronic mucocutaneous candidiasis (CMC) infection, autoimmune disorders, and infections leading to an early death.
CMC is a rare genetic condition occurring in childhood that affects immune responses against a type of yeast called Candida, the most common cause of fungal infections worldwide. It is characterized by recurrent and persistent infections, which may affect the nails, skin, and mucous membranes such as those in the mouth and genitals.
Notably, a previous international study reported that 21% of people with STAT1 gain-of-function mutations had bronchiectasis. Additional research has suggested that this may be related to a deficiency in a particular subset of immune cells called switched memory B-cells.
Now, researchers in China identified a new STAT1 gain-of-function mutation in a 17-year-old boy with CMC and bronchiectasis.
The boy showed signs of developmental delay relative to his peers and had a history of recurrent aphthous stomatitis — in the form of canker sores — in the mouth and bacterial lung infections, since childhood.
At age 10, he was infected with varicella-zoster virus — the cause of chickenpox — and developed pus-filled cavities in the lungs. Five years later, he was diagnosed with bronchiectasis and had increased blood levels of IgA. The patient received antiviral treatments and antibiotics to manage his infections.
At age 17, he was shorter than boys of the same age. At that time, he was treated at the hospital for repeated coughing and was prescribed oral antibiotics.
A battery of tests was then conducted to identify the potential cause of his condition, which allowed clinicians to rule out common autoimmune diseases and cancer. Notably, he still showed bronchiectasis and higher-than-normal levels of IgA in the blood.
“Since the examinations could not clarify the original cause of the patient’s condition and the patient has been ill since childhood, the possibility of genetically related disease was considered,” the researchers wrote.
Genetic analysis revealed the presence of a new missense, gain-of-function mutation (c.986C>G) in the STAT1 gene. Missense mutations lead to a change in a single amino acid — the building blocks of proteins — in the resulting protein.
Further analyses classified this newly identified mutation as likely disease causative.
The mutation was not detected in either parent, indicating that it was not inherited but rather occurred during embryonic development.
The team said that the patient’s symptoms were consistent with those reported for this type of mutation. They added that this was the first report describing slower development in a patient with STAT1 gain-of-function mutations.
“We propose that patients with unexplained chronic aphthous stomatitis, pulmonary bacterial infections, bronchiectasis and an increase in immunoglobulin IgA may carry STAT1 [gain-of-function] mutations,” the researchers wrote.
“This report describes the first patient carrying a pathogenic [disease-causing] variant of the STAT1 gene causing CMC infection, bronchiectasis, elevated serum IgA levels and stunting,” the team concluded.
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