Scientists find cause of rare devastating, autoimmune disease in Puerto Ricans—but also find potential treatment

A rare autoimmune condition with a tongue-twister of a name may impact people of Puerto Rican heritage through a newly discovered genetic pathway, a discovery that may ultimately guide genetic counseling and treatment, scientists associated with the discovery say.

The name of the disorder is autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, but doctors simply refer to the condition by its acronym, APECED. People affected are subject to severe autoimmune attacks against the endocrine glands, but the disorder leaves hardly any tissues or organs unscathed. Patients are particularly vulnerable to infections caused by various Candida species, the most common cause of fungal infections worldwide.

In general, APECED is described not only as rare, but potentially lethal and is triggered in most people who have it by so-called bi-allelic mutations. That means mutations are present in each allele—both copies—of a gene called AIRE. Each parent contributes one copy of all genes that make up the human genome.

Yet in a study of 104 patients, conducted by researchers at the Laboratory of Clinical Immunology and Microbiology at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, scientists identified a small subset of those patients—17—with a newly recognized genetic sequence that causes the disease. Of those 17 patients, 15 were of Puerto Rican ancestry.

“APECED is a life-threatening monogenic autoimmune disorder,” asserted Dr. Sebastian Ochoa, lead author of the study, published in Science Translational Medicine. Ochoa refers to the gene, AIRE, as the monogenic cause of the autoimmune disorder. No other gene undergoes mutations to cause APECED. But Ochoa and the NIAID team have identified a new mutation that causes the condition.

AIRE gets its acronym from its role: autoimmune regulator gene—AIRE, which underlies a cascade of deleterious events. The most insidious of those events is the proliferation of a highly reactive population of T cells.

These constituents of the immune system morph into veritable rogues. Like all T cells, their name is derived from the first letter of “thymus,” because of the gland from which these cells emerge. When APECED-associated T cells exit the thymus, they’re poised for recklessness and destruction, taking aim at a vast array of tissues, glands and organs.

Among the symptoms of the disorder are skin rashes; alopecia; alternating bouts of chronic diarrhea and constipation; kidney problems; Addison’s disease, which affects the adrenal glands; damaged tooth enamel, and high blood pressure. Dry eye is common among people with APECED. So too is keratitis, an inflammatory condition of the corneas, which can lead to blindness if left untreated.

In advanced stages, APECED can be complicated by kidney failure, sepsis, and squamous-cell oral and esophageal cancers. Overall, the disorder is considered quite rare because it is estimated that 1 in every 100,000 to 500,000 people are at risk.

Ethnic groups with a noteworthy APECED risk include Finnish, Sardinian, and Iranian Jewish populations. For those groups, an estimated one in 9,000 to 25,000 people are at risk. And while a genetic flaw in the AIRE gene underlies the disorder, it is a mechanism long associated with the condition.

Among the 17 members in the study’s subset, Ochoa and colleagues identified an AIRE gene miscue relative to a newly identified genetic variant. The team also found, at least in the laboratory, that this form of APECED may be reversible, a finding that paves the way toward more intensive study—and possibly an effective treatment.

Because of the cluster of Puerto Rican patients in the study, Ochoa and colleagues say their research has opened a new window of understanding about the underlying genetics of APECED in this ethnic group. Indeed, the high proportion of the newly found AIRE variant among Puerto Ricans suggests it may be a founder variant brought to the island from the Cádiz region of Spain.

“Our findings revealed [this variant] as a founder APECED-causing AIRE variant in the Puerto Rican population,” Ochoa wrote in Science Translational Medicine.

For all 17 patients, the flawed AIRE variant was tucked in a region of the gene’s non-coding RNA, sometimes called the dark matter of the genome. To understand what came next in their research, it is necessary to delve into the processes and jargon of genomics.

Deep in one of AIRE’s non-coding introns, Ochoa and colleagues discovered a cryptic splice site. A splice site is where the intron—the non-coding sequence of RNA is snipped out automatically when new messenger RNA strands are produced. That leaves an exon, a coding sequence free to be joined to the rest of the RNA exon coding sequence to produce a mature messenger RNA (mRNA) strand. The mature mRNA then possesses the instructions for a cell to make a specific protein.

Among Puerto Ricans, a healthy mRNA strand wasn’t being produced. The team found that the cryptic splice site led to the formation of a pseudoexon in AIRE, an exon that is not normally spliced into mRNA. The pseudoexon prompted the production of a non-functioning protein.

The researchers reversed this effect in cells by developing an antisense oligonucleotide that targeted the pseudoexon
region and restored normal splicing. Although further research and testing for safety and efficacy are needed, the antisense oligonucleotide may lay the groundwork for a therapeutic treatment, the team of researchers said.

Ochoa and collaborators concluded that the new findings can help guide counseling and symptom treatment for the gene-driven autoimmune disorder.

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