| CMD GENE DISCOVERY
THE FORSYTH INSTITUTE
Contact:
Dorothy Allen: The Forsyth Institute 617-262-5200 x398 dallen@forsyth.org
John Lacey: Harvard Medical School 617-432-0442 john_lacey@hms.harvard.edu
April 19, 2001
For Immediate Release:
RESEARCHERS DISCOVER GENETIC CAUSE OF BONE DISORDER DEPICTED IN FEATURE FILM
"MASK"
Boston----Researchers from the
Harvard School of Dental Medicine and Forsyth Institute joint Department of Oral Biology
have discovered a genetic mutation that appears to cause a rare bone disorder in the head
and face that can lead to blindness, deafness and paralysis of facial muscles.
The disorder, known as
craniometaphyseal dysplasia (CMD), was depicted in a 1985 movie called Mask, in which the
actress Cher played the mother of a teenage character who suffered from the disease.
The Harvard-Forsyth discovery,
described in this week’s online edition of The American Journal of Human Genetics,
concerns cell mechanisms involved in the transport of minerals to the bones. Ongoing
related research may one day yield important keys to understanding and treating
osteoporosis and other bone disorders.
The research team, headed by Ernst
Reichenberger, Ph.D., instructor, and Bjorn R. Olsen, M.D., Ph.D., chairman, both of the
HSDM-Forsyth Department, discovered several genetic mutations which affect a protein
involved in the transport of inorganic phosphates from osteoblasts (bone forming cells) to
the bone.
In mice, the lack of this protein
has been shown to cause ankylosis, or stiffening of the joints.
In humans, the researchers
determined, the mutations cause CMD, which is characterized by progressive thickening and
increased mineral density of craniofacial bones (bones of the head and face) and
abnormally shaped long bones. The gene and the associated mutant protein are called
"ANK"--the protein that causes ankylosis in mice.
Patients with CMD generally have
facial characteristics including a wide nasal bridge, hypertelorism (very wide set eyes)
and a prominent forehead.
In CMD, the excessive mineralization
of the bones begins just after birth, Reichenberger explains. First, the base of the skull
becomes very dense and increasingly thick. With increasing mineralization, the thickening
eventually takes over the entire skull. This process continues throughout a patient’s
lifetime. Even in children the thickening prevents normal remodeling of the skull and
causes a narrowing of the cranial foramina-- perforations in bones for nerves to pass
through. As a result, optical, facial and auditory nerves can become compressed, which can
lead to severe visual and neurological impairment such as blindness, facial palsy and
deafness. Other results include impaired jaw movement and nasal stenosis, which can cause
breathing problems. Because of the hard bone some teeth may erupt abnormally or not at
all.
According to John Mulliken, MD,
director of craniofacial surgery at Children's Hospital in Boston, the discovery is
"incredibly exciting" because it holds the promise of eventually developing
treatments or even averting the development of CMD.
Currently, Mulliken explains, the
only treatment for CMD is the surgical "burring down" of excess bone, much like
a carpenter hones down a piece of wood. The surgery is often difficult and may need to be
repeated many times over the course of a patient's lifetime, because, usually, the excess
bone grows back. "Discovering a gene is more exciting than performing hundreds of
operations," Mulliken said, because "it could potentially help generations to
come."
Olsen points out that while CMD
appears to affect only some 100 individuals in ten families described in scientific
journals worldwide, understanding the mechanism by which the mutation operates could have
important ramifications for understanding other bone diseases such as osteoporosis--in
which there is too little mineralization-- and osteopetrosis, in which there is too much.
The Harvard-Forsyth scientists spent
five years in this genetic research before discovering mutations in the ANK gene and the
associated mutant transmembranous protein. The ANK protein, found in many cell types, is
thought to be involved in transport of inorganic cell matter from the inside of the cell
to the outside.
The researchers’ quest involved
calling hospitals, dentists and surgeons worldwide in order to find five families where
CMD is inherited as an autosomal dominant disorder, as well as some individuals where CMD
develops spontaneously. They then determined on which chromosome the disease gene is
located, and investigated several different genes to determine which genes might be
involved in CMD.
"We knew that in mice with
normal ANK protein there is a certain concentration of inorganic phosphate (pyrophosphate)
in bone, which regulates the mineralization of bone , " said Ernst Reichenberger, who
leads the project. Mice that lack the ANK protein exhibit excessive mineralization in
their joint cartilage, which leads eventually to stiffening of their joints.
In CMD, if you don't have proper
transport from bone building cells to the bone matrix, you get a higher ratio of mineral
content in this bone. In CMD patients, the bone is so dense that it probably cannot be
degraded by osteoclasts, cells that normally break down bone. While the mechanisms for
this transport are as yet not clear, the researchers determined that the ANK protein is
involved in transport of inorganic phosphate from the osteoblasts to the bone, and that
mutant ANK protein interferes with normal pyrophosphate transport.
The researchers hope that, in the
future, they will be able to discover how the mutations interfere with normal function of
the ANK protein, and how inorganic phosphates regulate mineralization. They hope that this
knowledge will lead to the development of drugs or treatments for CMD and other bone
disorders.
Dominick DePaola, D.M.D., Ph.D.,
Forsyth’s president and CEO, said of the new breakthrough, "The identification
of this genetic mutation is a seminal discovery that could advance the diagnosis and
treatment of CMD as well as other birth defects. This discovery is a perfect example of
how a global interdisciplinary team of investigators can work together, led by Forsyth and
Harvard researchers, to solve these complex genetic problems."
Reichenberger is assistant member of
the staff at The Forsyth Institute and an instructor in the Harvard-Forsyth Department of
Oral Biology at Harvard School of Dental Medicine. Olsen is senior member of the staff at
the Forsyth Institute and professor and chair of Oral Biology in the Harvard-Forsyth
Department. Their article, "Autosomal Dominant Craniometaphyseal Dysplasia is Caused
By Mutations in the Transmembrane Protein ANK," is available by The Forsyth
Institute.
Other members of the Harvard-Forsyth
research team included: Valdenize Tiziani, of the Universidade Federal de Sao Paulo EPM
and Instituto de Cirurgia Plastica Craniofacial SOBRAPAR, Campinas, Brazil Shoji Watanabe
also of the Department of Plastic and Reconstructive Surgery, Showa University School of
Medicine in Tokyo, Japan, Lucy Park, Yasuyoshi Ueki, Carla Sanntanna; Scott T. Baur, also
of the Department of Genetics at Harvard Medical School; Rita Shiang, also of the
Department of Human Genetics, Medical College of Virginia, Richmond, VA; Peter Beighton,
Jessica Gardner, Herman Hamersma, Sean Sellars and Rajkumar Ramesar, all of the Department
of Human Genetics, University of Cape Town Medical School, Observatory, South Africa;
Andrew C. Lidra of the Department of Orthodontics, Ohio State University, College of
Dentrist, Columbus, OH; Annmarie Sommer of the Department of Genetics, Childrens Hospital,
Columbus, OH; Cassio M. Raposo doAmaral of the Universidade Federal de Sao Paulo--EPM and
Instituto de Cirurgia Plastica Craniofacial SOBRAPAR, Campinas, Brazil.
The research was funded by grants
from the National Institute of Health and from the John Butler Mulliken Foundation, which
was founded by Dr. Mulliken to help advance work on craniofacial disorders.
The Harvard-Forsyth Department of
Oral Biology is a joint program of the Harvard Medical School, and the Harvard School of
Dental Medicine, and The Forsyth Institute, an independent oral research and education
organization focused on oral and craniofacial science.
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