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Joseph R. Bishop, Manuela Schuksz, Jeffrey D. Esko
Heparan sulphate proteoglycans reside on the plasma membrane of all animal cells studied so far
and are a major component of extracellular matrices. Studies of model organisms and human
diseases have demonstrated their importance in development and normal physiology. A recurrent
theme is the electrostatic interaction of the heparan sulphate chains with protein ligands, which
affects metabolism, transport, information transfer, support and regulation in all organ systems.
The importance of these interactions is exemplified by phenotypic studies of mice and humans
bearing mutations in the core proteins or the biosynthetic enzymes responsible for assembling the
heparan sulphate chains.
SUMMARY: Heparan sulphate proteoglycans reside on the plasma membrane of all animal cells
studied so far and are a major component of extracellular matrices. Studies of model organisms
and human diseases
CONTEXT: hereditary multiple exostoses, an autosomal dominant disease characterized by the
formation of cartilage-capped bony outgrowths (osteochondromas or exostoses) on growth plates
throughout the body. Heterozygous mice also develop...
Nature 446, 1030 - 1037 (25 Apr 2007) Insight
Heparan sulphate proteoglycans reside on the plasma membrane of all animal cells studied so far
and are a major component of extracellular matrices. Studies of model organisms and human
diseases have demonstrated their importance in development and normal physiology. A recurrent
theme is the electrostatic interaction of the heparan sulphate chains with protein ligands, which
affects metabolism, transport, information transfer, support and regulation in all organ systems.
The importance of these interactions is exemplified by phenotypic studies of mice and humans
bearing mutations in the core proteins or the biosynthetic enzymes responsible for assembling the
heparan sulphate chains.
SUMMARY: Heparan sulphate proteoglycans reside on the plasma membrane of all animal cells
studied so far and are a major component of extracellular matrices. Studies of model organisms
and human diseases
CONTEXT: hereditary multiple exostoses, an autosomal dominant disease characterized by the
formation of cartilage-capped bony outgrowths (osteochondromas or exostoses) on growth plates
throughout the body. Heterozygous mice also develop...
Nature 446, 1030 - 1037 (25 Apr 2007) Insight
Osteochondroma / Exostoses Out Line Link (*****You should read these papers, when
you would like to understand MHE / MO / HME research better*****)
you would like to understand MHE / MO / HME research better*****)
Yu Yamaguchi, Ph.D.
Burnham Institute in La Jolla, California:
My laboratory has been studying the role of EXT1/heparan sulfate in mouse embryonic
development. We have created a conditional EXT1 knockout mouse model. These conditional
EXT1 knockout mice are being used for genetic studies to figure out how the deficiency of
EXT1/heparan sulfate causes MHE.
These conditional knockout mice, which allow knocking out EXT1 at the site and time of
researchers' desire, are very useful for diverse studies on the function of EXT1/heparan sulfate.
Dr. Yamaguchi and his lab have been able to distribute these mice to more than 20 laboratories
around the world (US, Europe, and Japan) to help studies by other MHE investigators. Using this
model system, Dr. Yamaguchi has demonstrated that mutations of EXT1 influence not only bones
but also the nervous system. Through an informal survey conducted by Sarah Ziegler and Dr.
Yamaguchi, although frequently ignored in the clinical front, MHE patients tend to have some
mental, neurological, and muscular symptoms. Such symptoms include: mild social interaction
deficits (excessive shyness, adherence to routines), heightened sensitivities to sensory stimulation
(sounds, touch, taste), difficulties to concentrate, sleep issues and muscle weakness(easy to get
tired) and pain. Dr. Yamaguchi believes these neurological symptoms can be explained by the
deficiency of heparan sulfate in nerve cells. Indeed, recent analysis of knockout mouse behavior
has revealed that these mice have deficits in certain aspects of learning and the levels of
fear/anxiety, as well as alterations in nerve cell wiring.
In addition, Dr. Yamaguchi has recently discovered that knockout of EXT1 in stem cells that
destined to become bones and cartilage causes severe bone abnormalities. These findings have
provided us with a new insight into the reason why MHE patients frequently associate a variety of
symptoms in addition to exostosis /osteochondroma formation, and suggests potential novel MHE
treatment paradigms.
Burnham Institute in La Jolla, California:
My laboratory has been studying the role of EXT1/heparan sulfate in mouse embryonic
development. We have created a conditional EXT1 knockout mouse model. These conditional
EXT1 knockout mice are being used for genetic studies to figure out how the deficiency of
EXT1/heparan sulfate causes MHE.
These conditional knockout mice, which allow knocking out EXT1 at the site and time of
researchers' desire, are very useful for diverse studies on the function of EXT1/heparan sulfate.
Dr. Yamaguchi and his lab have been able to distribute these mice to more than 20 laboratories
around the world (US, Europe, and Japan) to help studies by other MHE investigators. Using this
model system, Dr. Yamaguchi has demonstrated that mutations of EXT1 influence not only bones
but also the nervous system. Through an informal survey conducted by Sarah Ziegler and Dr.
Yamaguchi, although frequently ignored in the clinical front, MHE patients tend to have some
mental, neurological, and muscular symptoms. Such symptoms include: mild social interaction
deficits (excessive shyness, adherence to routines), heightened sensitivities to sensory stimulation
(sounds, touch, taste), difficulties to concentrate, sleep issues and muscle weakness(easy to get
tired) and pain. Dr. Yamaguchi believes these neurological symptoms can be explained by the
deficiency of heparan sulfate in nerve cells. Indeed, recent analysis of knockout mouse behavior
has revealed that these mice have deficits in certain aspects of learning and the levels of
fear/anxiety, as well as alterations in nerve cell wiring.
In addition, Dr. Yamaguchi has recently discovered that knockout of EXT1 in stem cells that
destined to become bones and cartilage causes severe bone abnormalities. These findings have
provided us with a new insight into the reason why MHE patients frequently associate a variety of
symptoms in addition to exostosis /osteochondroma formation, and suggests potential novel MHE
treatment paradigms.
Jeffrey D. Esko, Ph.D.
University of California, San Diego:
“Hereditary multiple exostoses (HME) is a dominant genetic disorder resulting in the formation of
generally benign cartilage-capped tumors in various bones.
Recent work from a number of laboratories indicates that the disease results from mutations in
EXT genes involved in making a complex sugar, or polysaccharide, called heparan sulfate.
Since heparan sulfate interacts with many factors involved in cell growth, this discovery may shed
light on the cause of the disease, which in turn may suggest new treatments.
Studies of HME have relied on analysis of human exostosis samples made available when patients
have surgery to remove problematic growths.
Progress understanding the cause of the disease has been frustrated by the paucity of material
available for study and only rare opportunities to compare the exostosis to normal tissue.
Recently, we discovered that mice bearing mutations in EXT genes also develop exostoses, which
mimic many key features of the human tumors.
One finding that emerged from studies of the HME mice is that the frequency of exostoses is
highly variable and depends on other genetic traits in the mice.
Since we can breed mice rapidly, we are now in a position to identify these other genes that may
contribute to the severity of the disease.
Additionally, we need to work out methods to detect exostoses in live animals, assess treatment
strategies for reducing the frequency and growth of exostoses, and develop systems to look at
exostosis development in isolated bones."
Dominique Stickens, Ph.D.
Mice deficient in Ext2 lack heparan sulfate and develop exostoses:
Stickens D, Zak BM, Rougier N, Esko JD, Werb Z.(Dominique Stickens), Department of Anatomy,
University of California, San Francisco, CA 94143-0452, USA.
Hereditary multiple exostoses (HME) is a genetically heterogeneous human disease characterized
by the development of bony outgrowths near the ends of long bones. HME results from mutations
in EXT1 and EXT2, genes that encode glycosyltransferases that synthesize heparan sulfate chains.
To study the relationship of the disease to mutations in these genes, we generated Ext2-null mice
by gene targeting. Homozygous mutant embryos developed normally until embryonic day 6.0,
when they became growth arrested and failed to gastrulate, pointing to the early essential role for
heparan sulfate in developing embryos.
Heterozygotes had a normal lifespan and were fertile; however, analysis of their skeletons showed
that about one-third of the animals formed one or more ectopic bone growths (exostoses)
Significantly, all of the mice showed multiple abnormalities in cartilage differentiation, including
disorganization of chondrocytes in long bones and premature hypertrophy in costochondral
cartilage.
These changes were not attributable to a defect in hedgehog signaling, suggesting that they arise
from deficiencies in other heparan sulfate-dependent pathways.
The finding that haploinsufficiency triggers abnormal cartilage differentiation gives insight into the
complex molecular mechanisms underlying the development of exostoses.
Dan Wells, Ph.D.
University of Houston:
Multiple Hereditary Exostoses (MHE) is an autosomal dominant skeletal disorder most frequently
caused by mutations in the EXT1 gene.
MHE affects proper development of endochondral bones, such that all affected individuals present
with exostoses adjacent to the growth plate of long bones, while some individuals exhibit
additional bone deformities. EXT1 functions as a heparan sulfate (HS) co-polymerase, and when
defective causes improper elongation of glycosaminoglycan side chains on core proteins of HS
proteoglycans.
Although analysis of heterozygous EXT1-deficient mice has failed to reveal any significant gross
morphological variations in skeletal development, significant alterations in molecular signaling occur
in the developing long bones.
Our results indicate that defects in EXT1 and the resulting reduction in HS lead to enhanced Indian
Hedgehog diffusion causing an increase in chondrocyte proliferation and delayed hypertrophic
differentiation.
Andrea Vortkamp, P.h.D.
Propagation of Ihh signaling:
One important question to understand the IhhP/THrP feedback loop is how the Ihh signal is
transported through the growth plate. In Drosophila the glycosyltransferase ‘tout velu’ (ttv) is
necessary to transport the hedgehog signal in the developing embryo.
Mutations in the human homologues, Ext-1 and Ext-2, result in, Heritable multiple exostoses’
(HME), disease characterized by benign bone tumors and short stature.In the developing bone we
found Ext-1 and Ext-2 both expressed in domains flanking the Ihh expression domain.
Using transgenic mice and a gene trap line targeting the Ext1 locus we aim to analyze the role of
Ext1 during bone devolopment and to identify a potential function in Ihh transport.
Propagation of Ihh signaling:
One important question to understand the IhhP/THrP feedback loop is how the Ihh signal is
transported through the growth plate. In Drosophila the glycosyltransferase ‘tout velu’ (ttv) is
necessary to transport the hedgehog signal in the developing embryo.
Mutations in the human homologues, Ext-1 and Ext-2, result in, Heritable multiple exostoses’
(HME), disease characterized by benign bone tumors and short stature.In the developing bone we
found Ext-1 and Ext-2 both expressed in domains flanking the Ihh expression domain.
Using transgenic mice and a gene trap line targeting the Ext1 locus we aim to analyze the role of
Ext1 during bone devolopment and to identify a potential function in Ihh transport.
Marion Kuche-Gullberg, Ph.D.
Characterization of enzymes involved in heparan sulfate biosynthesis:
Our area of interest is the structure and function of heparan sulfate (HS). HSs play dynamic
functional roles in a diverse number of biological events related to intracellular signaling, cell-cell
interactions and tissue morphogenesis.
HS execute its function by the binding to a variety of molecules including growth factors, serine
protease inhibitors and extracellular matrix proteins.
The biological activities of HS largely depend on the amount and distribution of its sulfate groups
that provide specific binding sites for proteins.
Our overall goal is to understand the mechanisms generating specific saccharide structures and to
provide insight into the link between cell type specific expression of HS modifying enzymes and the
biological function of the polysaccharide.
Our research focus on
1. UDP-glucose dehydrogenase, which converts UDP-glucose to UDP-glucuronic acid providing one
of the building blocks for chain elongation
2. heparan sulfate polymerases (EXT1 and EXT2) giving rise to the polysaccharide backbone(mice
with a gene trap mutation in Ext)
3. 2-O- and 6-O-sulfotransferases, incorporating sulfate groups in specific positions, generating
biological active heparan sulfate.
4. Sulfs, cell associated HS 6-O endosulfatases, that remove sulfate groups in specific positions,
thus modulating HS dependent growth factor signaling.
Howard Hughes Medical Institute Holiday Lectures on Science Programs. This four part lecture
series held in 2002 will give you a better insight and understanding of research that is now being
conducted in MHE now. Once you have viewed these 4 lectures you can view other illustrations on
this web-page. Click this link
series held in 2002 will give you a better insight and understanding of research that is now being
conducted in MHE now. Once you have viewed these 4 lectures you can view other illustrations on
this web-page. Click this link
| What is a chondrocyte |
Chondrocytes (from Greek chondros cartilage + kytos cell) are the only cells found in cartilage.
They produce and maintain the cartilaginous matrix, which consists mainly of collagen and
proteoglycans.
To view a short video of what is chondrocyte is please click the tab
They produce and maintain the cartilaginous matrix, which consists mainly of collagen and
proteoglycans.
To view a short video of what is chondrocyte is please click the tab
Slide from video presentation " What is MHE Research?" by Jeffrey D. Esko, Phd
| Jeffrey D. Esko, Ph.D. "What is MHE Research" Click Here to view this video presentation |
This presentation will open in a new browser window
Heparan Sulfates - Regulators of Cell
Functions
Heparan sulfates (HS): are glycans (complex
sugars) found on all cell surfaces which act by
binding selectively to a variety of proteins
and pathogens and are critically relevant to many
disease processes (eg. , inflammation,
neurodegeneration, angiogenesis, wound
healing, cancer, cardiovascular disordersand
infectious diseases). Many of these activities
have been detected using heparin, which is a
subclass of the HS family of glycans .
Functions
Heparan sulfates (HS): are glycans (complex
sugars) found on all cell surfaces which act by
binding selectively to a variety of proteins
and pathogens and are critically relevant to many
disease processes (eg. , inflammation,
neurodegeneration, angiogenesis, wound
healing, cancer, cardiovascular disordersand
infectious diseases). Many of these activities
have been detected using heparin, which is a
subclass of the HS family of glycans .
Heparin and heparan sulphates act by binding
to proteins and regulating their biological activities.
The picture shows the interaction of a small
heparin hexasaccharide (6 sugar units) with the
growth factor called basic FGF that controls the
growth and differentiation of many cell types.
The HS family of sugars are composed of long
chains of repeating disaccharide units of uronic
acid and glucosamine residues, decorated by
variable patterns of sulphate and carboxyl groups,
giving them very strong negative charge.
They are produced in living cells by a complex
multi-step enzymatic biosynthetic process.
Heparin is a highly sulphated and relatively
structurally homogenous molecule compared to
cellular heparan sulphates, which have increased
sequence diversity and fulfil many complex
biological functions by interacting with proteins
and influencing their biological activities.
chains of repeating disaccharide units of uronic
acid and glucosamine residues, decorated by
variable patterns of sulphate and carboxyl groups,
giving them very strong negative charge.
They are produced in living cells by a complex
multi-step enzymatic biosynthetic process.
Heparin is a highly sulphated and relatively
structurally homogenous molecule compared to
cellular heparan sulphates, which have increased
sequence diversity and fulfil many complex
biological functions by interacting with proteins
and influencing their biological activities.
Animated picture shows an extended helical
heparin sequence with sulphate groups
(yellow/red) decorating the backbone
(image courtesy of Dr Barbara Mulloy,
National Institiute of Biological Standards,
Herts, UK)
heparin sequence with sulphate groups
(yellow/red) decorating the backbone
(image courtesy of Dr Barbara Mulloy,
National Institiute of Biological Standards,
Herts, UK)
HS and heparin are produced on cells by a
complex process involving the sequential action
of multiple enzymes which knit together the
repeating disaccharide units (polymerases) and
then modify them with exquisitely complex
patterns of sulphate groups
(sulfotransferases). The resulting structural
motifs bind to specific proteins and influence
their biological activities.
complex process involving the sequential action
of multiple enzymes which knit together the
repeating disaccharide units (polymerases) and
then modify them with exquisitely complex
patterns of sulphate groups
(sulfotransferases). The resulting structural
motifs bind to specific proteins and influence
their biological activities.
Heparan sulphate binds proteins
Heparin and heparan sulphates act by binding
to proteins and regulating their biological
activities.
The picture shows the interaction of a small
heparin hexasaccharide (6 sugar units) with the
growth factor called basic FGF that controls the
growth and differentiation of many cell types.
Heparin and heparan sulphates act by binding
to proteins and regulating their biological
activities.
The picture shows the interaction of a small
heparin hexasaccharide (6 sugar units) with the
growth factor called basic FGF that controls the
growth and differentiation of many cell types.
heparan sulfate proteoglycans (HSPGs), are ubiquitous glycoproteins present at the cell surface
and in the extracellular matrix, and have their roles in neuron migration, process outgrowth and
guidance and in synapse formation. HSPGs contain a protein core substituted with heparan
sulphate (HS) polysaccharide chains, which encode complex sugar sequences with variant sulfation
patterns that confer biological functions as protein regulators. HS/HSPGs play essential roles in
controlling cell differentiation, tissue morphogenesis and homeostasis. In the nervous system, HS
and HSPGs have been implicated in neuron migration, axon guidance, synapse formation and
maturation and control of physiological responses such as feeding, learning and memory.
and in the extracellular matrix, and have their roles in neuron migration, process outgrowth and
guidance and in synapse formation. HSPGs contain a protein core substituted with heparan
sulphate (HS) polysaccharide chains, which encode complex sugar sequences with variant sulfation
patterns that confer biological functions as protein regulators. HS/HSPGs play essential roles in
controlling cell differentiation, tissue morphogenesis and homeostasis. In the nervous system, HS
and HSPGs have been implicated in neuron migration, axon guidance, synapse formation and
maturation and control of physiological responses such as feeding, learning and memory.
HS/heparin structure
HS and heparin are long, linear chains of
sugars, composed of repeating disaccharide
units made up of alternating uronic acid
(glucuronic or iduronic acid) and glucosamine
residues. The backbone structure is then
decorated with complex patterns of sulphate
groups at various positions.
HS and heparin are long, linear chains of
sugars, composed of repeating disaccharide
units made up of alternating uronic acid
(glucuronic or iduronic acid) and glucosamine
residues. The backbone structure is then
decorated with complex patterns of sulphate
groups at various positions.
For more detailed information concerning the Perichondrium, chondrocytes, PTHrP, Ihh
and other signaling pathways affected by the defect in the EXT genes please view the
video link below.
To view this video presentation given by Dr. Henry Kronenberg during this conference please click
the link tab
The MHE Research would like to thank all for the use of the presentation of The
Perichondrium in Bone Development on the MHE Research Foundation website. This
presentation was from the April 25–28, 2007, the 2nd Conference on Skeletal Biology
and Medicine held in NYC.
This meeting, was jointly hosted at the New York Academy of Sciences and Mount Sinai School of
Medicine, was organized and chaired by Mone Zaidi, professor of endocrinology, geriatrics and
adult development, and structural and chemical biology at Mount Sinai. Cochairs were Gerard
Karsenty of Columbia University and Steven Teitelbaum of the Washington University School of
Medicine.
and other signaling pathways affected by the defect in the EXT genes please view the
video link below.
To view this video presentation given by Dr. Henry Kronenberg during this conference please click
the link tab
The MHE Research would like to thank all for the use of the presentation of The
Perichondrium in Bone Development on the MHE Research Foundation website. This
presentation was from the April 25–28, 2007, the 2nd Conference on Skeletal Biology
and Medicine held in NYC.
This meeting, was jointly hosted at the New York Academy of Sciences and Mount Sinai School of
Medicine, was organized and chaired by Mone Zaidi, professor of endocrinology, geriatrics and
adult development, and structural and chemical biology at Mount Sinai. Cochairs were Gerard
Karsenty of Columbia University and Steven Teitelbaum of the Washington University School of
Medicine.
Henry H. Roehl, Ph.D.
Department of Biomedical Science, The University of Sheffield, United Kingdom
The Roehl laboratory focuses on the role of heparin sulphate proteoglycans (HSPGs) during
development of the zebrafish. Although HSPGs are ubiquitous structural components of the
extracellular matrix, they are also thought to play very specific roles in cell-cell signalling during
development. The disaccharide repeats that make up the heparan chains come in 32 different
varieties making heparan sulphate the most information-dense biopolymer found in nature.
Binding studies and X-ray crystallography have identified many specific interactions between
oligosaccharides and secreted proteins. Mutational analysis of genes involved with proteoglycan
synthesis has shown that Wingless, Decapentaplegic, Fibroblast Growth Factor and Hedgehog
signalling pathways all depend on proteoglycans at different times during Drosophila development.
These data together have led to the hypothesis that different HSPGs have highly specialized roles
including limiting or facilitating signal diffusion, blocking signal degradation and modulating
signal/receptor complex formation.
Our work in this field began with the positional cloning of a small family of zebrafish mutants that
all have similar phenotypes suggesting that their gene products interact or are in the same
pathway. These genes, pinscher (pic/papst1), boxer (box/extl3) and dackel(dak/ext2), are all
required for development of the pectoral fins, sorting of the retinotectal projections and
morphogenesis of the skeleton. This cloning project has been a collaboration between three
groups (Chi-Bin Chien, U. of Utah; Robert Geisler, M.P.I. Tuebingen; Henry Roehl, U. of Sheffield).
Together, we have found that box and dak encode glycosyltransferases responsible for synthesis
of the heparin sugar chain (EXTL3 and EXT2 respectively), and pic encodes a sulphur transporter
that is involved with the sulphation of all proteogycans (PAPST1). These finding have allowed us to
begin to address the functional requirements of HSPGs during zebrafish development.
Recently we have turned our attention to the role of HSPGs play in a disease called Hereditary
Multiple Exostoses (HME). HME is an autosomal dominant disorder that affects 1 in 50,000 among
the general population. Patients with HME have a short stature and develop numerous
cartilage-capped tumours (called exostoses or osteochondromas) from the growth plates of their
longbones. Mutations in human EXT2 account for a large percentage of the cases of this disease.
While osteochondromas are normally benign, they can lead to complications and patients have a
1-2% risk of developing chondrosarcoma or osteosarcoma. The dominant and sporadic nature of
tumour formation in HME patients has led to the proposal of two genetic models.
Osteochondromas may arise from a loss of heterozygosity (LOH) at one of the EXT loci in a
developing chondrocyte resulting in unregulated growth and clonal expansion. In support of this
model, somatic mutations or aneuploidy have been found in 3 out of 46 osteochondromas
analysed. The alternative model is that reduced EXT gene dose results in a structural change that
allows chondrocytes to occasionally escape normal developmental constraints to give rise to an
osteochondroma.
Department of Biomedical Science, The University of Sheffield, United Kingdom
The Roehl laboratory focuses on the role of heparin sulphate proteoglycans (HSPGs) during
development of the zebrafish. Although HSPGs are ubiquitous structural components of the
extracellular matrix, they are also thought to play very specific roles in cell-cell signalling during
development. The disaccharide repeats that make up the heparan chains come in 32 different
varieties making heparan sulphate the most information-dense biopolymer found in nature.
Binding studies and X-ray crystallography have identified many specific interactions between
oligosaccharides and secreted proteins. Mutational analysis of genes involved with proteoglycan
synthesis has shown that Wingless, Decapentaplegic, Fibroblast Growth Factor and Hedgehog
signalling pathways all depend on proteoglycans at different times during Drosophila development.
These data together have led to the hypothesis that different HSPGs have highly specialized roles
including limiting or facilitating signal diffusion, blocking signal degradation and modulating
signal/receptor complex formation.
Our work in this field began with the positional cloning of a small family of zebrafish mutants that
all have similar phenotypes suggesting that their gene products interact or are in the same
pathway. These genes, pinscher (pic/papst1), boxer (box/extl3) and dackel(dak/ext2), are all
required for development of the pectoral fins, sorting of the retinotectal projections and
morphogenesis of the skeleton. This cloning project has been a collaboration between three
groups (Chi-Bin Chien, U. of Utah; Robert Geisler, M.P.I. Tuebingen; Henry Roehl, U. of Sheffield).
Together, we have found that box and dak encode glycosyltransferases responsible for synthesis
of the heparin sugar chain (EXTL3 and EXT2 respectively), and pic encodes a sulphur transporter
that is involved with the sulphation of all proteogycans (PAPST1). These finding have allowed us to
begin to address the functional requirements of HSPGs during zebrafish development.
Recently we have turned our attention to the role of HSPGs play in a disease called Hereditary
Multiple Exostoses (HME). HME is an autosomal dominant disorder that affects 1 in 50,000 among
the general population. Patients with HME have a short stature and develop numerous
cartilage-capped tumours (called exostoses or osteochondromas) from the growth plates of their
longbones. Mutations in human EXT2 account for a large percentage of the cases of this disease.
While osteochondromas are normally benign, they can lead to complications and patients have a
1-2% risk of developing chondrosarcoma or osteosarcoma. The dominant and sporadic nature of
tumour formation in HME patients has led to the proposal of two genetic models.
Osteochondromas may arise from a loss of heterozygosity (LOH) at one of the EXT loci in a
developing chondrocyte resulting in unregulated growth and clonal expansion. In support of this
model, somatic mutations or aneuploidy have been found in 3 out of 46 osteochondromas
analysed. The alternative model is that reduced EXT gene dose results in a structural change that
allows chondrocytes to occasionally escape normal developmental constraints to give rise to an
osteochondroma.
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Please note more research publications can be located on researchers foundation website pages
The MHE Research Foundation is proud to be working with the EuroBoNeT consortium, a European Commission
granted Network of Excellence for studying the pathology and genetics of bone tumors.
granted Network of Excellence for studying the pathology and genetics of bone tumors.
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Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
By the Health On the Net Foundation. Click here to verify.# HON Conduct 282463 and is linked on the NIH
National Library of Medicine, Directory of Health Organizations (SIS) website, as well as the link for Patient
Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
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The information provided here is for educational and informational purposes only. This website does not engage in the practice
of medicine. In all cases we recommend that you consult your own physician regarding any course of treatment or medicine.
This website is regularly reviewed by members of the Scientific and Medical Advisory Board of the MHE Research Foundation.
This web page was updated last on 2/20/08, 4:00 pm Eastern time
| Names of researchers listed on this webpage |