|
Mutational analysis of EXT1 and EXT2 genes and a newsystem for “grading”
clinical expression of disease in patients with Hereditary Multiple Exostoses.
Abstract 2005 MHE Conference
1Luca Sangiorgi, 2Nicola Fabbri, 2Laura Campanacci,1Elena Pedrini,
1Veronica Maini, 1Silvia Capponcelli, 1Marina Mordenti and
2Mario Mercuri.1Genetics Unit, 2V Surgery Division,
Rizzoli Orthopedic Institute, Bologna, Italy.
Introduction: Several mutations dispersed throughout the EXT1 and EXT2 genes have been identified in HME patients. Most
of these are responsible of the truncation of EXT1 or EXT2 proteins which are likely to become inactive and degrade rapidly,
resulting in a nearly complete loss-of-function. A prospective longitudinal study was undertaken to correlate genotype and
phenotype of the disease in families and sporadic cases, with the purpose of defining the disease spectrum of expression.
Method: A multidisciplinary clinic, involving geneticists and orthopaedic surgeons, is weekly carried out at the Rizzoli Institute.
In order to evaluate the spectrum and distribution of mutations leading to HME in the Rizzoli cohort of patients, a new multi-
step DHPLC-based mutation screening method was optimised. For informative families, we adopted a pre-screening linkage
analysis to selectively focus the DHPLC testing on either EXT1 or EXT2. Patient clinical assessment is carried out using a new
classification system substantially based on deformity and functional limitation and the genotype-phenotype study is performed
using this system.
Results: In a small pilot we enrolled 36 unrelated probands, representing 20 families and 14 sporadic cases for the presence of
mutations in either EXT1 or EXT2 genes. Thirty-one out of 36 probands (86%) had mutations either in EXT1 (24/31; 77%) or
EXT2 (7/31; 23%), mainly distributed in the amino-terminal region of the proteins and the vast majority of them are
responsible of a premature protein truncation.
Most mutations were distributed towards the 5’ end of EXT1 and EXT2 genes.In accordance with the most recent data, 23 of
31 mutations (74%) were novel. No novel missense or splice site mutations were detected in 200 control chromosomes. All
splice site mutations were present in the highly conserved AG and GT positions of the splice acceptor and donor junctions, and
only one of these (c.IVS6+1G>T in the EXT1 gene) had been previously reported in the HGMD database. The 3 missense
mutations clustered within exon 2 of the EXT1 gene and caused amino acid substitutions in residues 339 and 340. Two of these
(c.1018C>T (p.R340C), c.1019G>A (p.R340H)) had been already described whereas the third one(c.1016G>T (p.G339V)) was a
novel mutation responsible for substitution of a glycine codon with a valine within an important key element for EXT1 function.
The overall mutation frequency in 36 probands was 86% (67% in EXT1 and 19% in EXT2). Mutations were found in 10 of 14
sporadic cases (71%) and in 20 of 21 familial cases (95%). No disease-causing mutation has been detected in 5 of 36 patients.
A new clinical classification based on clinical evaluation and orthopaedic problems has been defined.
A preliminary study performed on 153 pts have shown that most (80%) are not substantially limited by the disease. Using the
DHPLC based screening technique and the clinical classification system, we are currently running a genotype/phenotype study
on 170 patients. Preliminary results indicate that mutations on specific exons of the EXT1 gene correlate with more relevant
clinical limitations.
Conclusions: Our results identified several novel and many private mutations in a large cohort of patients, confirming the
strong allelic heterogeneity of EXT1 and EXT2 genes. Our optimised DHPLC-based approach represents a reliable, efficient and
highly sensitive diagnostic strategy for rapid detection of germline mutations in HME patients. The genotype-phenotype study is
giving indication regarding association of alterations and clinical presentation of the disease.
clinical expression of disease in patients with Hereditary Multiple Exostoses.
Abstract 2005 MHE Conference
1Luca Sangiorgi, 2Nicola Fabbri, 2Laura Campanacci,1Elena Pedrini,
1Veronica Maini, 1Silvia Capponcelli, 1Marina Mordenti and
2Mario Mercuri.1Genetics Unit, 2V Surgery Division,
Rizzoli Orthopedic Institute, Bologna, Italy.
Introduction: Several mutations dispersed throughout the EXT1 and EXT2 genes have been identified in HME patients. Most
of these are responsible of the truncation of EXT1 or EXT2 proteins which are likely to become inactive and degrade rapidly,
resulting in a nearly complete loss-of-function. A prospective longitudinal study was undertaken to correlate genotype and
phenotype of the disease in families and sporadic cases, with the purpose of defining the disease spectrum of expression.
Method: A multidisciplinary clinic, involving geneticists and orthopaedic surgeons, is weekly carried out at the Rizzoli Institute.
In order to evaluate the spectrum and distribution of mutations leading to HME in the Rizzoli cohort of patients, a new multi-
step DHPLC-based mutation screening method was optimised. For informative families, we adopted a pre-screening linkage
analysis to selectively focus the DHPLC testing on either EXT1 or EXT2. Patient clinical assessment is carried out using a new
classification system substantially based on deformity and functional limitation and the genotype-phenotype study is performed
using this system.
Results: In a small pilot we enrolled 36 unrelated probands, representing 20 families and 14 sporadic cases for the presence of
mutations in either EXT1 or EXT2 genes. Thirty-one out of 36 probands (86%) had mutations either in EXT1 (24/31; 77%) or
EXT2 (7/31; 23%), mainly distributed in the amino-terminal region of the proteins and the vast majority of them are
responsible of a premature protein truncation.
Most mutations were distributed towards the 5’ end of EXT1 and EXT2 genes.In accordance with the most recent data, 23 of
31 mutations (74%) were novel. No novel missense or splice site mutations were detected in 200 control chromosomes. All
splice site mutations were present in the highly conserved AG and GT positions of the splice acceptor and donor junctions, and
only one of these (c.IVS6+1G>T in the EXT1 gene) had been previously reported in the HGMD database. The 3 missense
mutations clustered within exon 2 of the EXT1 gene and caused amino acid substitutions in residues 339 and 340. Two of these
(c.1018C>T (p.R340C), c.1019G>A (p.R340H)) had been already described whereas the third one(c.1016G>T (p.G339V)) was a
novel mutation responsible for substitution of a glycine codon with a valine within an important key element for EXT1 function.
The overall mutation frequency in 36 probands was 86% (67% in EXT1 and 19% in EXT2). Mutations were found in 10 of 14
sporadic cases (71%) and in 20 of 21 familial cases (95%). No disease-causing mutation has been detected in 5 of 36 patients.
A new clinical classification based on clinical evaluation and orthopaedic problems has been defined.
A preliminary study performed on 153 pts have shown that most (80%) are not substantially limited by the disease. Using the
DHPLC based screening technique and the clinical classification system, we are currently running a genotype/phenotype study
on 170 patients. Preliminary results indicate that mutations on specific exons of the EXT1 gene correlate with more relevant
clinical limitations.
Conclusions: Our results identified several novel and many private mutations in a large cohort of patients, confirming the
strong allelic heterogeneity of EXT1 and EXT2 genes. Our optimised DHPLC-based approach represents a reliable, efficient and
highly sensitive diagnostic strategy for rapid detection of germline mutations in HME patients. The genotype-phenotype study is
giving indication regarding association of alterations and clinical presentation of the disease.
Dr. Sangiorgi serves on the Scientific and Medical Advisory Board of the MHE Research Foundation
Research authored by Dr. Sangiorgi
Click the tab and a window will appear.
List of Publications via PubMed
(NIH National Library of Medicine)
Research authored by Dr. Sangiorgi
Click the tab and a window will appear.
List of Publications via PubMed
(NIH National Library of Medicine)
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| Luca Sangiorgi, M.D., Ph.D., research |
Press Release 1 / 19 / 08
Mutation Screening of EXT1 and EXT2 by Denaturing High-Performance Liquid Chromatography, Direct Sequencing
Analysis, Fluorescence in Situ Hybridization, and a New Multiplex Ligation-Dependent Probe Amplification Probe Set
in Patients with Multiple Osteochondromas
Ivy Jennes*, Mark M. Entius{dagger}, Els Van Hul*, Alessandro Parra{ddagger}, Luca Sangiorgi {ddagger} and Wim Wuyts*
To Read this publication Click Here
Both Luca Sangiorgi, M.D., Ph.D. and Wim Wuyts, Ph.D. are members of our Scientific & Medical Advisory Board and our
foundation helped support this research
Mutation Screening of EXT1 and EXT2 by Denaturing High-Performance Liquid Chromatography, Direct Sequencing
Analysis, Fluorescence in Situ Hybridization, and a New Multiplex Ligation-Dependent Probe Amplification Probe Set
in Patients with Multiple Osteochondromas
Ivy Jennes*, Mark M. Entius{dagger}, Els Van Hul*, Alessandro Parra{ddagger}, Luca Sangiorgi {ddagger} and Wim Wuyts*
To Read this publication Click Here
Both Luca Sangiorgi, M.D., Ph.D. and Wim Wuyts, Ph.D. are members of our Scientific & Medical Advisory Board and our
foundation helped support this research
Questions to the Scientific & Medical Advisory Board,
Please use the contact Scientific & Medical Advisory Board Tab or you may email directly
AdvisoryBoard@mheresearchfoundation.org
Please use the contact Scientific & Medical Advisory Board Tab or you may email directly
AdvisoryBoard@mheresearchfoundation.org
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2009 Conference abstract
Genotype-Phenotype Correlation Study in 529 MO Patients: 'Protective' and 'Risk' Factors
Pedrini E.1, Jennes I.2, Tremosini M.1, Mordenti M.1, Parra A.1, Pignotti E.3, Wuyts W.2, and Sangiorgi L.1
1Department of Medical Genetics, Rizzoli Orthopaedic Institute, Bologna, Italy. 2Department of Medical Genetics, University and
University Hospital of Antwerp, Belgium. 3Section of Statistics, Rizzoli Orthopaedic Institute, Bologna, Italy.
e-mail: luca.sangiorgi@ior.it
Multiple Osteochondroma (MO [MIM 133700]) is a genetic disorder characterized by a large spectrum of related EXT mutations
and a wide clinical heterogeneity. To evaluate if the severity of disease and the risk of malignant degeneration are linked with a
specific genetic background we performed a genotype-phenotype correlation study analyzing the larger MO case study ever
collected. To estimate the constancy of what observed and substantiate the statistical significance of the data we compared
results coming from two different European MO reference centers (the department of Medical Genetics of Bologna, IOR and
University Hospital of Antwerp).
Clinical parameters were evaluated using a new clinical classification repeatable and easy to apply, based on deformity and
functional limitations caused by lesions. The study was performed on a total of 529 MO patients (405 from IOR and 124 from
Antwerp) ranging from 2 to 83 years old and representing 344 probands with their available affected relatives. The presence of
mutations in EXT1 (8q24) or EXT2 (11p11-12) genes was investigated with a combined DHPLC/MLPA protocol screening with a
direct sequencing of all abnormal profile. Statistical analyses were performed considering the two case studies both separately
and on the whole; all collected data were then analyzed to define ‘protective’ and ‘risk’ factors related with mild or severe clinical
presentations.
Molecular analyses revealed 344 EXT1 and 132 EXT2 mutations; no disease causing mutation was found in 51 patients. This
study confirmed the predominant role of EXT1 in defining a severe clinical phenotype characterized also by short stature.
Adverse clinical presentation is associated also with sporadic cases and male gender. Interestingly, patients without EXT1/2
detected mutations are significantly related to mild phenotypes, with a stature closely approximating to the average population
height. Malignant transformation was observed in 26 patients; there is no evidence of any association between chondrosarcoma
occurrence and EXT1 mutations, number of lesions and the severity of disease. Interestingly, malignant degeneration mainly
occurred in patients with a positive family history (only 2 were classified as sporadic cases).
The comprehensive study, beside the intrinsic limitations of multicentric revisions, shows that trends observed in the IOR has
been confirmed in the Antwerp patients substantiating the statistical significance of the data; this leads to consider MO
information obtained in this study as probable constant features of disease and therefore could play a relevant role in the clinical
approach to MO patients (providing information to be offer during genetic counselling, calibrating follow-up program for each
group of patients and helping in defining appropriate clinical treatment) except for prevention of malignant transformation where
a regular screening is still highly recommended. Since individuals with identical mutation often show quite different phenotypes,
the presence of other factors which can modulate the clinical presentation of MO is evident; therefore, another goal of this study
consists in the definition of clinical and genetic homogeneous group of patients where appropriate studies could be performed in
order to clarify this feature and better characterize the pathogenesis of the disease.
Genotype-Phenotype Correlation Study in 529 MO Patients: 'Protective' and 'Risk' Factors
Pedrini E.1, Jennes I.2, Tremosini M.1, Mordenti M.1, Parra A.1, Pignotti E.3, Wuyts W.2, and Sangiorgi L.1
1Department of Medical Genetics, Rizzoli Orthopaedic Institute, Bologna, Italy. 2Department of Medical Genetics, University and
University Hospital of Antwerp, Belgium. 3Section of Statistics, Rizzoli Orthopaedic Institute, Bologna, Italy.
e-mail: luca.sangiorgi@ior.it
Multiple Osteochondroma (MO [MIM 133700]) is a genetic disorder characterized by a large spectrum of related EXT mutations
and a wide clinical heterogeneity. To evaluate if the severity of disease and the risk of malignant degeneration are linked with a
specific genetic background we performed a genotype-phenotype correlation study analyzing the larger MO case study ever
collected. To estimate the constancy of what observed and substantiate the statistical significance of the data we compared
results coming from two different European MO reference centers (the department of Medical Genetics of Bologna, IOR and
University Hospital of Antwerp).
Clinical parameters were evaluated using a new clinical classification repeatable and easy to apply, based on deformity and
functional limitations caused by lesions. The study was performed on a total of 529 MO patients (405 from IOR and 124 from
Antwerp) ranging from 2 to 83 years old and representing 344 probands with their available affected relatives. The presence of
mutations in EXT1 (8q24) or EXT2 (11p11-12) genes was investigated with a combined DHPLC/MLPA protocol screening with a
direct sequencing of all abnormal profile. Statistical analyses were performed considering the two case studies both separately
and on the whole; all collected data were then analyzed to define ‘protective’ and ‘risk’ factors related with mild or severe clinical
presentations.
Molecular analyses revealed 344 EXT1 and 132 EXT2 mutations; no disease causing mutation was found in 51 patients. This
study confirmed the predominant role of EXT1 in defining a severe clinical phenotype characterized also by short stature.
Adverse clinical presentation is associated also with sporadic cases and male gender. Interestingly, patients without EXT1/2
detected mutations are significantly related to mild phenotypes, with a stature closely approximating to the average population
height. Malignant transformation was observed in 26 patients; there is no evidence of any association between chondrosarcoma
occurrence and EXT1 mutations, number of lesions and the severity of disease. Interestingly, malignant degeneration mainly
occurred in patients with a positive family history (only 2 were classified as sporadic cases).
The comprehensive study, beside the intrinsic limitations of multicentric revisions, shows that trends observed in the IOR has
been confirmed in the Antwerp patients substantiating the statistical significance of the data; this leads to consider MO
information obtained in this study as probable constant features of disease and therefore could play a relevant role in the clinical
approach to MO patients (providing information to be offer during genetic counselling, calibrating follow-up program for each
group of patients and helping in defining appropriate clinical treatment) except for prevention of malignant transformation where
a regular screening is still highly recommended. Since individuals with identical mutation often show quite different phenotypes,
the presence of other factors which can modulate the clinical presentation of MO is evident; therefore, another goal of this study
consists in the definition of clinical and genetic homogeneous group of patients where appropriate studies could be performed in
order to clarify this feature and better characterize the pathogenesis of the disease.
2009 Conference abstract
Osteochondroma Onset and Malignant Degeneration: Redefinition of EXT Gene Role
Monia Zuntini1*, Elena Pedrini1*, Alessandro Parra1, Marco Alberghini2, Federica Sgariglia1, and Luca Sangiorgi1
1Department of Medical Genetics and 2Anatomy and Pathological Histology Unit, Rizzoli Orthopaedic Institute, Bologna, Italy.
e-mail: elena.pedrini@ior.it
Osteochondroma is the most common of the benign tumors of the bone. It could presents as a single lesion, solitary
osteochondroma (SO) with an incidence of 1-2%, whereas it occurs as multiple lesions in the context of multiple
osteochondroma disease (MO, incidence of 1/50000). The most severe complication of osteochondroma is the malignant
transformation into secondary peripheral chondrosarcoma (CHS); it is estimated to be rare in SO (<1%) whereas it occurs in
1-5% of MO patients. Even if both conditions have been associated with mutations in EXT1 and EXT2 genes, the molecular
mechanism involved in osteochondroma onset and malignant progression is still contradictory.
To evaluate whether a second mutational hit is required for the development of solitary/multiple osteochondromas and/or their
malignant degenerations, we investigated 65 tissue samples, including 46 osteochondromas (35 MO and 11 SO) and 17
peripheral chondrosarcomas (12 derived from MO and 5 from SO) with 2 recurrences, for the presence of both point mutations
and big rearrangements in EXT1/EXT2 genes; mutational screening was performed with a combined DHPLC/MLPA protocol
including also direct sequencing of all abnormal profiles and quantitative Real Time qPCR to validate MLPA results. Analyses were
performed also on corresponding constitutional blood samples. For 5 patients we considered more resections from different
affected skeletal sites.
6 out of 11 SO samples showed the presence of point or big mutations in EXT1 gene whereas 5 showed no EXT mutations; no
samples with two mutational hit were observed. Mutational screening of 35 MO samples confirmed all the presence of the
germ-line mutation found in constitutional DNA; 30 samples (86%) showed only this heterozygous mutation, while a second
mutational hit was found in 5 tissues. Analyzing malignant degeneration, 3 out of 5 SO-related chondrosarcomas showed no
additional somatic mutation, while in 2 primary tumour resections the loss of one copy of EXT1 or EXT2 gene was detected; the
corresponding recurrence of this latter sample showed the loss of both EXT2 alleles. 5 out of 12 CHS resections derived from
MO showed the presence of a second EXT1/2 somatic mutational hit; in the only available recurrence the heterozygous germline
mutation was found at homozygous status due to the loss of the wt allele.
Our results show the absence of a second mutational hit in most of analyzed MO and SO samples suggesting that their growth
may not necessarily require two EXT1/2 genetic alterations, which seems to be a common prerequisite for malignant
transformation and tumour progression. All these evidences lead to the hypothesis of the presence of molecular mechanisms
alternative to EXT inactivation in MO pathogenesis, as mutations/polymorphisms in EXT regulatory sequences,
post-transcriptional regulation pathways or involvement of other genes not belonging to EXT family.
Osteochondroma Onset and Malignant Degeneration: Redefinition of EXT Gene Role
Monia Zuntini1*, Elena Pedrini1*, Alessandro Parra1, Marco Alberghini2, Federica Sgariglia1, and Luca Sangiorgi1
1Department of Medical Genetics and 2Anatomy and Pathological Histology Unit, Rizzoli Orthopaedic Institute, Bologna, Italy.
e-mail: elena.pedrini@ior.it
Osteochondroma is the most common of the benign tumors of the bone. It could presents as a single lesion, solitary
osteochondroma (SO) with an incidence of 1-2%, whereas it occurs as multiple lesions in the context of multiple
osteochondroma disease (MO, incidence of 1/50000). The most severe complication of osteochondroma is the malignant
transformation into secondary peripheral chondrosarcoma (CHS); it is estimated to be rare in SO (<1%) whereas it occurs in
1-5% of MO patients. Even if both conditions have been associated with mutations in EXT1 and EXT2 genes, the molecular
mechanism involved in osteochondroma onset and malignant progression is still contradictory.
To evaluate whether a second mutational hit is required for the development of solitary/multiple osteochondromas and/or their
malignant degenerations, we investigated 65 tissue samples, including 46 osteochondromas (35 MO and 11 SO) and 17
peripheral chondrosarcomas (12 derived from MO and 5 from SO) with 2 recurrences, for the presence of both point mutations
and big rearrangements in EXT1/EXT2 genes; mutational screening was performed with a combined DHPLC/MLPA protocol
including also direct sequencing of all abnormal profiles and quantitative Real Time qPCR to validate MLPA results. Analyses were
performed also on corresponding constitutional blood samples. For 5 patients we considered more resections from different
affected skeletal sites.
6 out of 11 SO samples showed the presence of point or big mutations in EXT1 gene whereas 5 showed no EXT mutations; no
samples with two mutational hit were observed. Mutational screening of 35 MO samples confirmed all the presence of the
germ-line mutation found in constitutional DNA; 30 samples (86%) showed only this heterozygous mutation, while a second
mutational hit was found in 5 tissues. Analyzing malignant degeneration, 3 out of 5 SO-related chondrosarcomas showed no
additional somatic mutation, while in 2 primary tumour resections the loss of one copy of EXT1 or EXT2 gene was detected; the
corresponding recurrence of this latter sample showed the loss of both EXT2 alleles. 5 out of 12 CHS resections derived from
MO showed the presence of a second EXT1/2 somatic mutational hit; in the only available recurrence the heterozygous germline
mutation was found at homozygous status due to the loss of the wt allele.
Our results show the absence of a second mutational hit in most of analyzed MO and SO samples suggesting that their growth
may not necessarily require two EXT1/2 genetic alterations, which seems to be a common prerequisite for malignant
transformation and tumour progression. All these evidences lead to the hypothesis of the presence of molecular mechanisms
alternative to EXT inactivation in MO pathogenesis, as mutations/polymorphisms in EXT regulatory sequences,
post-transcriptional regulation pathways or involvement of other genes not belonging to EXT family.
Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database
(MOdb).
Jennes I, Pedrini E, Zuntini M, Mordenti M, Balkassmi S, Asteggiano CG, Casey B, Bakker B, Sangiorgi L, Wuyts W.
Hum Mutat. 2009 Oct 6
Nov 17, 2009
Luca Sangiorgi, M.D., Ph.D., is a member of the foundations Scientific & Medical Advisory Board.
" BOLOGNA, Italy, Nov. 17 /PRNewswire-FirstCall/ -- IBM (NYSE: IBM) announced today that its Research scientists are
working with the Rizzoli Orthopedic Institute, in Bologna, Italy, to use information technology to better address treatment
and research for rare genetic skeletal diseases"
| Photo's taken during the Third International MHE Research Conference |
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Click here to verify.# HON Conduct 282463 and is the patient support link on the US Government Genetics Home Reference (http://ghr.nlm.nih.gov)
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Intute: health & life sciences a free online service providing access to the very best Web resources for education and research located in the UK
Click here to verify.# HON Conduct 282463 and is the patient support link on the US Government Genetics Home Reference (http://ghr.nlm.nih.gov)
website, also linked for Patient Information on The Diseases Database a cross-referenced index of human disease, as well as 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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Identification and functional characterization of the human EXT1 promoter region.
Jennes I, Zuntini M, Mees K, Palagani A, Pedrini E, De Cock G, Fransen E, Vanden Berghe W, Sangiorgi L, Wuyts W.
Gene. 2012 Jan 15;492(1):148-59. Epub 2011 Oct 19.
Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT
genes inactivation.
Zuntini M, Pedrini E, Parra A, Sgariglia F, Gentile FV, Pandolfi M, Alberghini M, Sangiorgi L.
Oncogene. 2010 Jul 1;29(26):3827-34.
Jennes I, Zuntini M, Mees K, Palagani A, Pedrini E, De Cock G, Fransen E, Vanden Berghe W, Sangiorgi L, Wuyts W.
Gene. 2012 Jan 15;492(1):148-59. Epub 2011 Oct 19.
Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT
genes inactivation.
Zuntini M, Pedrini E, Parra A, Sgariglia F, Gentile FV, Pandolfi M, Alberghini M, Sangiorgi L.
Oncogene. 2010 Jul 1;29(26):3827-34.