CONTACT: JENNIFER BROWN
Iowa City IA 52242
(319) 335-9917; fax(319) 384-4638
Release: July 25, 2002
Studies Find Basis For Brain Defects In Some Muscular Dystrophies
Piecing together a biochemical and genetic puzzle, University of Iowa researchers
and their colleagues have revealed a new molecular mechanism that appears
to be the root cause of a subset of muscular dystrophies.
Most muscular dystrophies, as the name suggests, weaken and destroy muscles.
However, dystrophies such as Fukuyama Congenital Muscular Dystrophy, Walker-Warburg
Syndrome (WWS) and Muscle-Eye-Brain (MEB) disease also involve brain abnormalities
that cause severe mental retardation in patients.
"They are an interesting group of dystrophies because they affect more
than just muscle," said Kevin Campbell, Ph.D., the Roy J. Carver Chair
of Physiology and Biophysics and interim head of the department, UI professor
of neurology, and a Howard Hughes Medical Institute (HHMI) Investigator.
The results of two new studies by Campbell and his colleagues, which appear
in the July 25 issue of the journal Nature, provide new diagnostic tools that
will help physicians make precise diagnoses and accurate prognoses for patients
with these congenital muscular dystrophies. The lead authors of the two papers
are Dan Michele, Ph.D., a UI postdoctoral fellow in physiology and biophysics
and neurology, and Steven Moore, M.D., Ph.D., UI professor of pathology and
a staff physician with the Veterans Affairs Medical Center in Iowa City.
"These results improve our understanding of muscular dystrophy, and
the more we understand, the better equipped we'll be to develop therapies,"
Campbell said. "The findings also are important for appropriate genetic
As genetic causes of muscular dystrophies have been discovered, a pattern
has emerged. Many muscular dystrophy-causing genetic mutations affect protein
components of the dystrophin-glycoprotein complex. This large complex of proteins
provides an essential bridge between structures inside and outside of cells
and appears to be critical for the physical integrity of muscle.
It seemed likely that a defective component of the complex also would cause
the dystrophies involving brain abnormalities.
In the Nature articles, Campbell and his colleagues show that dystroglycan,
a protein in the complex, is the key player in these dystrophies, but not
because of any defect in the protein itself.
Rather, the genetic defect lies in enzymes normally responsible for adding
sugar residues to this core protein -- a process known as glycosylation. As
a result, certain sugars are not added to dystroglycan.
Although Campbell discovered dystroglycan more than 10 years ago, this is
the first time it has been directly implicated in muscular dystrophy. Over
the years, the Campbell lab has developed antibody probes to analyze dystroglycan.
Using these antibodies, Michele and his colleagues showed that dystroglycan
protein is present in muscle cells of patients with Fukuyama and MEB disease.
However, the protein does not have its full complement of sugar attachments.
The team further found that the abnormal glycosylation pattern prevents dystroglycan
from interacting with its normal biological partners, such as laminin molecules,
at the surface of cells in muscle and brain.
"When Kevin's laboratory started studying the biochemistry of dystroglycan,
we had no idea that it might be clinically relevant and yet now those studies
allow us to describe these clinical diseases," Michele said.
While Michele and his colleagues were pursuing the biochemical clues about
how dystroglycan functions in cells, Moore set out to determine the role of
dystroglycan in brain function.
Using sophisticated genetic techniques, the UI scientists created mice that
specifically lacked dystroglycan in their brains. The team then examined the
mice and found severe brain development defects, which closely resembled the
brain defects in humans with Fukuyama, WWS and MEB. This convinced the research
group that dystroglycan dysfunction was indeed responsible for brain abnormalities
in patients with congenital muscular dystrophies.
"When the brain develops normally, neurons are generated near the center
of the brain and then migrate out towards the surface to form a normal cerebral
cortex," Moore explained. "In both the congenital muscular dystrophies
and the mouse deletion-model that we made, that migration is abnormal. Simply
by deleting the protein (dystroglycan) from brain, we can mimic the brain
developmental abnormalities present in patients with the congenital muscular
Campbell added that the findings also might implicate disruption of dystroglycan
function in other genetic and acquired neurological disorders where errors
in neuronal migration are involved.
The new information that dystroglycan and its glycosylation are involved
in neuronal migration also is important for understanding normal brain development.
Moore, working with former UI professor Toshinori Hoshi, Ph.D., further
showed that the absence of brain dystroglycan disrupted a brain process known
as long-term potentiation in the mice. This process is associated with the
strengthening of connections between brain cells, which in turn influences
learning and memory. So, it appears that mice lacking this protein have brain
deficits, which likely impair learning and memory. This suggests that dystroglycan
has a role in brain function beyond that of neuronal migration.
In addition to their biochemical studies of dystroglycan, Michele and his
colleagues also examined the brains of another mouse model of muscular dystrophy
known as the myd mouse. As in the human diseases, the genetic defect of the
myd mouse disrupts the biochemical process that adds sugar units to dystroglycan.
And like the human diseases, the defect disrupts interactions between dystroglycan
and its biological partners.
Although the myd mouse is an established model of muscular dystrophy, no
one had looked at how the defect affected the brain. When Michele and his
colleagues investigated, they found brain abnormalities that look like the
developmental defects seen in humans who have congenital muscular dystrophies
such as Fukuyama Congenital Muscular Dystrophy.
Thus, two lines of research converged to implicate errors in dystroglycan
glycosylation as the cause of brain developmental abnormalities seen in the
human congenital muscular dystrophies. The research indicates that there are
disrupted connections between the important dystrophin-glycoprotein complex
and other biological components in both muscle and brain of patients with
Fukuyama and MEB disease and the myd mouse. These findings support Campbell's
hypothesis that the complex is critical, and disruptions results in muscular
The studies were funded in part by the Howard Hughes Medical Institute,
the National Institutes of Health, and the Muscular Dystrophy Association.
In addition to involving UI researchers, the two studies included scientists
at Albany Medical College, Johns Hopkins University, the University of Wisconsin,
the National Institute of Neuroscience, Tokyo, and Helsinki University Hospital.
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.