|Lack of Key Enzyme Associated with Development of Rare Tumor
Researchers at the National Institutes of Health have discovered
that a rare tumor of the adrenal glands appears to result from
a genetic deficiency of an important enzyme. The enzyme is one
of a class of enzymes involved in halting a cell’s response
to hormones and appears to stop cells from dividing.
The study, published in Nature Genetics, was conducted by researchers
in NIH’s National Institute of Child Health and Human Development.
The NIH group collaborated with scientists from the Mayo Clinic,
the Cochin Institute in Paris, the University of Paris, Ohio State
University in Columbus, and the Universitaire Vaudois in Lausanne,
Switzerland, in collecting samples from patients with rare adrenal
disorders. Scientists from Sapio Sciences in York, Pennsylvania,
assisted in the analysis of the data.
In conducting the study, the researchers used gene arrays to analyze
the DNA of patients with a rare tumor of the adrenal glands, known
as micronodular adrenocortical hyperplasia, explained the study’s
senior author, Constantine Stratakis, M.D., D(Med)Sc, Chief of
NICHD’s Section on Endocrinology and Genetics. The researchers
also used the technology to analyze samples of the patients’ tumors.
The researchers found four patients who had mutant copies of a
gene that contains the information for Phosphodiesterase 11A (PDE11A).
Phosphodiesterases are a family of enzymes involved in “switching
off” a cell’s response to hormones, Dr. Stratakis explained.
For a hormone to affect the cell, it must first bind to a molecule,
or receptor, on the cell’s surface, analogous to how a key
fits into a lock. This action triggers the cell to produce substances
known as cyclic nucleotides. These function as “second messengers,” often
stimulating the cell to begin an activity. In the case of adrenal
cells, cyclic nucleotides, such as cyclic AMP and cyclic GMP, may
stimulate cell growth or other activities. Once the activity has
ended, phosphodiesterases degrade the cyclic nucleotides, thereby
halting the cell’s response to the hormone.
In the study, the patients’ tumors were made up of cells
that were deficient in the enzyme PDE11A. This enzyme halts cyclic
nucleotide production in adrenal cells as well as in other kinds
of cells in the body. Because they lacked PDE11A, the patients’ adrenal
cells had higher levels of cyclic nucleotides. The researchers
believe that these higher cyclic nucleotide levels led to the formation
The gene for PDE11A contains the information needed to make 4
slightly different forms of the enzyme. The form of the enzyme
that was mutated in the patients who took part in the study was
found in large amounts in normal adrenal glands and in even larger
amounts in normal prostate glands, Dr. Stratakis added. Other forms
of PDE11A are found in several other tissues, including the testes,
skeletal muscle, and the heart.
Dr. Stratakis noted that although the evidence associating the
mutation in the gene for PDE11A to the development of adrenal tumors
was very strong, the study was not capable of proving that the
mutation actually caused the tumors.
In their article, the researchers wrote that drugs used to treat
erectile dysfunction interfere with the functioning of PDE11A.
The researchers noted that PDE11A “is partially inhibited” by
the drug tadalafil and “weakly” inhibited by sildenafil.
They added that there are no reports in the medical literature
of malfunctioning adrenal glands or increased adrenal cell growth
in users of these drugs.
“However, detailed clinical studies addressing this potential
complication are currently lacking,” they wrote.
Dr. Stratakis and his colleagues are currently planning studies
to determine if differences in the gene for PDE11A might influence
an individual’s cancer risk.
The NICHD sponsors research on development, before and after birth;
maternal, child, and family health; reproductive biology and population
issues; and medical rehabilitation. For more information, visit
the Institute’s Web site at http://www.nichd.nih.gov/.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.