BALTIMORE—The understanding of cystic fibrosis (CF) etiology has been greatly advanced by the discovery and cloning of the gene for CF transmembrane conductance regulator (CFTR), whose function is thought to be eliminated in patients with classic CF and reduced in those with nonclassic disease. Yet a recent paper described patients lacking mutations in the CFTR gene who were clinically indistinguishable from those with nonclassic CF.[1]

In its full-blown form, CF is characterized by chronic bacterial airways and sinus infection, poor fat digestion due to pancreatic dysfunction, an elevated sweat chloride concentration (typically, 90 to 110 mmol/L), and a malformed vas deferens in male patients. But approximately 10% of those diagnosed with CF display a less severe, or nonclassic, form of the disease: These patients have sweat chloride levels that range from less than 40 mmol/L (normal) to 90 mmol/L, they generally retain pancreatic function, and their organ systems may be affected to a lesser degree than those of classic CF patients. Traditionally, “mild disease in CF (the nonclassic form) is associated with one or two mutations that permit some [CFTR] function,” explained Garry R. Cutting, MD, Professor in the Institute of Genetic Medicine at Johns Hopkins University School of Medicine in Baltimore.

CFTR: NOT THE WHOLE STORY?

“We’ve always thought of CF being due to defects in one gene,” said Dr. Cutting. He and his colleagues received referrals of patients believed to have nonclassic CF, “yet after a pretty thorough search, we were unable to find mutations in either [copy] of the gene associated with this disease,” he told PULMONARY REVIEWS. “We had difficulty ourselves believing it initially,” he remarked.

Dr. Cutting and his colleagues performed extensive genetic analysis on 74 nonclassic CF patients. They found that 29 of the patients had two mutations in the CFTR gene, as expected. Surprisingly, however, in 30 of the 74 patients, no mutation in either CFTR gene was found. The researchers next measured cyclic AMP-dependent ion and fluid transport in the sweat glands and nasal epithelium of some of these patients. Based on the results, “CFTR appears to be functioning normally,” said Dr. Cutting. “We did look at mRNA, and transcription of the CFTR genes also appeared to be normal,” he added.

In 15 patients, the researchers found only one mutant gene copy. Such patients may “have a defect in CFTR plus a defect somewhere else … and the combination of the two now creates the phenotype,” Dr. Cutting suggested. Curiously, no significant difference in clinical features or in chloride sweat concentration was seen among patients with none, one, or two CFTR mutations.

“Half of the patients who had no mutations met diagnostic criteria for the disorder on the basis of elevated sweat chloride concentrations and in clinical features,” Dr. Cutting noted. “Interestingly, only half of the patients with mutations in each copy of the gene met current diagnostic criteria.” The work thus challenges our definition of CF as well as our explanations of the disease’s etiology. “We hope to provoke further study … as to other etiologies, and at the same time, to provoke clinicians to decide how we’re going to classify CF,” Dr. Cutting remarked.

—Mimi Zucker, PhD

Reference
1. Groman JD, Meyer ME, Wilmott RW, et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002;347:401-407.

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