Scientists discover genetic cause of rare autoimmune disease

A team of international scientists has discovered the genetic basis of a rare hereditary autoimmune disease, according to a study recently published in Scientific translational medicine.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening autoimmune disease that affects approximately 1 in 100,000 to 500,000 people worldwide, according to the National Institutes of Health.

People with APECED may experience more than 30 different manifestations of the disease, including chronic fungal infections of the skin and mouth, endocrine dysfunction, and multiorgan inflammation.

Although the disease is known to have genetic causes, not all affected patients have the characteristic AIRE gene variant, said Jennifer Miller, MD, ’04 GME, associate professor of pediatrics in the Division of Endocrinology, who was co-author of the study.

“We saw a patient in clinic with APECED and we knew she had this clinical picture, but we didn’t know why because all of her genetic tests were normal,” Miller said.

As part of the study, scientists from several countries around the world carried out genetic sequencing of 17 patients who had APECED but did not have the expected genetic variants. They found that the genetic variance resided in the non-coding region of the AIRE gene, according to the study.

“It is not a variant of the expressed gene, but a non-coding region within the gene, which causes frameshifting and failure of AIRE gene function, leading to the same clinical picture APECED than the one we observe with previously known AIRE variants.” » Miller said.

By analyzing kidney and thymus cells cultured with the AIRE mutation, investigators found that the variant altered the AIRE protein, disrupting normal function.

According to the study, 15 of the 17 participants were of Puerto Rican ancestry, a finding that could facilitate future screening of patients with APECED.

“We have so many genetic tests at our fingertips now, and it’s amazing to be able to get diagnoses based on genetics. But it tells me that if you have someone who fits a clinical scenario, even if their genetics “What you would expect, that doesn’t mean there isn’t an underlying genetic variant, just that we may not have tested for it,” said Miller.

Miller hopes to build on this work to improve treatment options for her patient, in hopes of obtaining insurance covering more effective and convenient medications for APECED-associated hypoparathyroidism, she said. declared.

“From a clinical perspective, the next step for me is to continue working with some of the authors of this paper to try to get medications approved for hypoparathyroidism in children as an alternative to conventional therapy, which is very tedious and involves taking multiple medications throughout the day,” Miller said.

Miller said she was grateful for the international collaboration that brought new answers to her patient.

“I had a patient and clinicians elsewhere had a patient, and we all found this research site and were able to create a strong, compelling story, which basically proves that this genetic change is responsible for the clinical picture of these patients ” Miller said. .