U-Iowa physician suggests possible enzyme deficiency in cystic fibrosis

June 24, 2003

IOWA CITY, Iowa -- Mucus that excessively accumulates in the lungs of patients with cystic fibrosis (CF) may be linked to the deficiency of an enzyme called arylsulfatase B. The deficiency may in turn be linked to the known genetic mutation in CF -- a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

The possible connection is proposed by Joanne Tobacman, M.D., University of Iowa assistant professor (clinical) of internal medicine, who reviewed 30 years of research about the enzyme and chemicals it normally metabolizes, or processes for use by the body. Tobacman's opinion article appears in the June 6 issue of CHEST: The Cardiopulmonary and Critical Care Journal of the American College of Chest Physicians.

"The CFTR gene is mutated in people with CF but the observed manifestations of the disease have not been fully explained by that genetic change," Tobacman said. "Mutations in the CFTR gene might reduce the arylsulfatase B activity."

The CFTR defect is known to alter a protein, causing problems in cellular channels that normally regulate salt and water secretions. The defective CFTR protein also affects other cellular processes. The first CFTR gene discovery was made in 1989. Tobacman drew on an even earlier observation by another researcher to draw a possible connection between CFTR and arylsulfatase B.

In 1970, Elizabeth Neufeld, Ph.D., formerly a researcher with the National Institutes of Health (now professor and chair of biological chemistry at the University of California at Los Angeles), found diminished sulfatase enzyme activity in the lymphoid cells lines of patients with CF.

Normally, arylsulfatase B metabolizes two sugar chains called dermatan sulfate and chondroitin-4 sulfate. However, when arylsulfatase B is absent or insufficient, these substances can build up and change the characteristics of secretions.

"These sulfated glycosaminoglycans, or GAGs can accumulate, altering the properties of secretions and making it more difficult to clear them," Tobacman said. "This predisposes people with CF to chronic infection."

Pseudomonas, a bacteria that often infects people with CF, makes sulfatase and may utilize the GAGs that are not metabolized because of insufficient arylsulfatase B. Thus, the extra GAGs may help this bacteria flourish.

Tobacman also noted that CF shares a few clinical characteristics with the recessive genetic disease Maroteaux-Lamy Syndrome, which is caused by complete or severe arylsulfatase B deficiency.

The article is accompanied by an editorial by Bruce Rubin, M.D., professor of pediatrics, medicine, medical engineering, physiology and pharmacology at Wake Forest University School of Medicine. Rubin writes, "CFTR is a large and complex channel, so it is not surprising that it would have diverse functions. The link between these functions of CFTR and CF disease remains a matter of speculation and debate."

The next step for Tobacman and colleagues will be to assess the impact of CFTR gene transfection on arylsulfatase B activity in CF cell lines. Transfection involves introducing a functional copy of the gene. Tobacman also will further explore the effect of sulfatase enzymes in clinical conditions. The chemical name of arylsulfatase B is N-acetylgalactosamine-4-sulfatase.

University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at www.uihealthcare.com.
ABSTRACT: The abstract of Dr. Joanne Tobacman's article, "Does Deficiency of Arylsulfatase B Have a Role in Cystic Fibrois?" (Chest. 2003;123:2130-2139) is at http://www.chestjournal.org/cgi/content/abstract/123/6/2130. It also is provided below:

Does Deficiency of Arylsulfatase B Have a Role in Cystic Fibrosis? Joanne K. Tobacman, MD
From the Department of Internal Medicine, University of Iowa Health Care, Iowa City, IA.

Cystic fibrosis (CF) is associated with mutation and abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR) that affects cellular chloride transport. Clinically, CF of the lung is associated with excessive accumulation of secretions, including the sulfated glycosaminoglycans, chondroitin sulfate and dermatan sulfate (DS), both of which contain sulfated N-acetylgalactosamine residues. The sulfatase enzymes, which are a highly conserved group of enzymes with high specificity for designated sulfate groups, include arylsulfatase B, a lysosomal enzyme. Arylsulfatase B, also known as N-acetyl galactosamine 4-sulfatase, can degrade DS and chondroitin-4 sulfate. Previously reported data demonstrated diminished activity of arylsulfatase B in lymphoid cell lines of patients with CF compared to normal control subjects. Frequent infections with Pseudomonas, a sulfatase-producing organism, occur in patients with CF, whereas infections with Mycobacterium tuberculosis, which lacks sulfatase activity, are infrequent. Additional investigation to determine if diminished function of arylsulfatase B is a consistent finding in cells of patients with CF may be informative, and may help to correlate the molecular, biochemical, and clinical characteristics of CF.

University of Iowa

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