| 2009 Conference - e- poster |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||
|
Multiple Hereditary Exostoses due to O-glycosylation defects: First clinical and molecular studies in Argentinean
patients.
Delgado, M.A., Asteggiano, C
Delgado, M.A. (1), Azar, N. (1), Zecchini L.(3), Becerra, A.(1), Bistué Millón, M.B. (1); Chiesa, M. (2); Robledo, H.(2); Sarrión, P.
(5); Dodelson de Kremer, R. (1); Ballcels, S (5); Grinberg, D.(5); Asteggiano, CG.(1,4). (1) CEMECO (Centro de Estudio de las
Metabolopatías Congénitas), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Hospital de Niños S.T., Córdoba,
Argentina; (2) Servicio de Imágenes, Hospital de Niños S.T., Córdoba, Argentina. (3) Servicio de Traumatología, Hospital de
Niños S.T., Córdoba, Argentina; (4) Cátedra Química Biológica, Facultad de Medicina, Universidad Católica de Córdoba,
Argentina; (5) Departamento de Genética, Facultad de Biología, Universidad de Barcelona, España.
e-mail: casteggi@campus1.uccor.edu.ar.
Congenital Disorders of Glycosylation (CDG) are an increasing chapter of multisystemic diseases. It has been described N-
glycosylation defects (classified as CDG-Type I and Type II) and includes Oglycosylation defects as the primary cause of a variety
of diseases, ranging from muscular dystrophies, chondrodysplasias and mucolipidosis I and II to the multiple hereditary
exostoses (MHE). MHE is an autosomal dominant bone disorder, the most common type of benign bone tumor. It is caused by
defects in the proteins encoded by two already identified genes: EXT1(8q24) and EXT2 (11p11.2). The proteins exostosin 1 and
2 are glycosyltransferases that form a heterooligomeric complex in Golgi, involved in the initiation of heparan sulphate (HS)
biosynthesis and in its elongation. HS is an O-glycosaminoglycan essential for cell signaling. Impaired HS biosynthesis results in
abnormal endochondral ossification leading to the formation of exostoses. These are clinically characterized by cartilage-capped
tumors (exostoses/osteochondromas) grows from the growth plates of long bones or from the surface of flat bones, and have
manifestations like orthopedic deformities of forearm, ankle, varus or valgus of knee, arthritis, vessels and nerves compression,
etc. The most important complication is malignant transformation in chondrosarcoma (3-5%). MHE has an estimated occurrence
of 1 in 50,000 in the general population. The solitary osteochondroma (SO) is approximately six times more common than the
occurrence of multiple osteochondroma (MO) and approximately 62% of the patients have a positive family history.
Aim: Application of a clinical and molecular protocol for the investigation of alterations in EXT1 and EXT2 genes in Argentinean
MHE patients and the study of the genotype-phenotype correlation for the eventual prediction of malignant transformation of
osteochondromas in chondrosarcoma.
Materials and Methods: In the present study we are investigating 12 Argentinean patients, 9 with MO and3 with SO, with a range
of the ages at time of diagnosis of 2-50 years old, 5 male and 7 female. Patientphenotype was obtained at the Bio-images and
Orthopedic Department and includes clinical and radiological parameters. Genotyping was performed from DNA of peripheral
blood and specific tissues(osteochondroma). Amplification of EXT1-EXT2 genes was performed by PCR and direct sequencing of
entire gene coding regions, including flanking intronic sequences.
Results: Four exonic changes were identified in EXT1 of patients with MO: 1) a novel nonsense mutation in exon 1 (c.848T>A; p.
L283X), resulting in a premature stop codon. This patient presented malignant transformation to chondrosarcoma, and we are
currently studying loss of heterozygosity (LOH) in the tumor’s DNA; 2) one missense mutation in exon 2 (c.1037G>C; p.
R346T); 3) a 1 bp deletion in exon 6 (c.1469delT, p.L490R) leading to a frameshift and a premature stop eight codons later; 4)
a nonsense mutation in exon 1 (substitution, c.748delT; p.F250F) with stop in the next codon (DNA change c.751del; p. L251X).
Discussion: The O-glycosylation defects are a new chapter in metabolic and genetic medicine. Our first results identified three
novel mutations all in EXT1 and the genetic defects in four patients. The clinical manifestation and molecular diagnosis allow us
to exclude other similar bone’s diseases and to associate mutations with malignant transformation of the affected tissues. MHE
seems to be in a high frequency in the Argentinean population and the progression in their studies will provide a wider vision of
this pathology in our country and Latin America. CONICET/FONCyT/UCC.
patients.
Delgado, M.A., Asteggiano, C
Delgado, M.A. (1), Azar, N. (1), Zecchini L.(3), Becerra, A.(1), Bistué Millón, M.B. (1); Chiesa, M. (2); Robledo, H.(2); Sarrión, P.
(5); Dodelson de Kremer, R. (1); Ballcels, S (5); Grinberg, D.(5); Asteggiano, CG.(1,4). (1) CEMECO (Centro de Estudio de las
Metabolopatías Congénitas), Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Hospital de Niños S.T., Córdoba,
Argentina; (2) Servicio de Imágenes, Hospital de Niños S.T., Córdoba, Argentina. (3) Servicio de Traumatología, Hospital de
Niños S.T., Córdoba, Argentina; (4) Cátedra Química Biológica, Facultad de Medicina, Universidad Católica de Córdoba,
Argentina; (5) Departamento de Genética, Facultad de Biología, Universidad de Barcelona, España.
e-mail: casteggi@campus1.uccor.edu.ar.
Congenital Disorders of Glycosylation (CDG) are an increasing chapter of multisystemic diseases. It has been described N-
glycosylation defects (classified as CDG-Type I and Type II) and includes Oglycosylation defects as the primary cause of a variety
of diseases, ranging from muscular dystrophies, chondrodysplasias and mucolipidosis I and II to the multiple hereditary
exostoses (MHE). MHE is an autosomal dominant bone disorder, the most common type of benign bone tumor. It is caused by
defects in the proteins encoded by two already identified genes: EXT1(8q24) and EXT2 (11p11.2). The proteins exostosin 1 and
2 are glycosyltransferases that form a heterooligomeric complex in Golgi, involved in the initiation of heparan sulphate (HS)
biosynthesis and in its elongation. HS is an O-glycosaminoglycan essential for cell signaling. Impaired HS biosynthesis results in
abnormal endochondral ossification leading to the formation of exostoses. These are clinically characterized by cartilage-capped
tumors (exostoses/osteochondromas) grows from the growth plates of long bones or from the surface of flat bones, and have
manifestations like orthopedic deformities of forearm, ankle, varus or valgus of knee, arthritis, vessels and nerves compression,
etc. The most important complication is malignant transformation in chondrosarcoma (3-5%). MHE has an estimated occurrence
of 1 in 50,000 in the general population. The solitary osteochondroma (SO) is approximately six times more common than the
occurrence of multiple osteochondroma (MO) and approximately 62% of the patients have a positive family history.
Aim: Application of a clinical and molecular protocol for the investigation of alterations in EXT1 and EXT2 genes in Argentinean
MHE patients and the study of the genotype-phenotype correlation for the eventual prediction of malignant transformation of
osteochondromas in chondrosarcoma.
Materials and Methods: In the present study we are investigating 12 Argentinean patients, 9 with MO and3 with SO, with a range
of the ages at time of diagnosis of 2-50 years old, 5 male and 7 female. Patientphenotype was obtained at the Bio-images and
Orthopedic Department and includes clinical and radiological parameters. Genotyping was performed from DNA of peripheral
blood and specific tissues(osteochondroma). Amplification of EXT1-EXT2 genes was performed by PCR and direct sequencing of
entire gene coding regions, including flanking intronic sequences.
Results: Four exonic changes were identified in EXT1 of patients with MO: 1) a novel nonsense mutation in exon 1 (c.848T>A; p.
L283X), resulting in a premature stop codon. This patient presented malignant transformation to chondrosarcoma, and we are
currently studying loss of heterozygosity (LOH) in the tumor’s DNA; 2) one missense mutation in exon 2 (c.1037G>C; p.
R346T); 3) a 1 bp deletion in exon 6 (c.1469delT, p.L490R) leading to a frameshift and a premature stop eight codons later; 4)
a nonsense mutation in exon 1 (substitution, c.748delT; p.F250F) with stop in the next codon (DNA change c.751del; p. L251X).
Discussion: The O-glycosylation defects are a new chapter in metabolic and genetic medicine. Our first results identified three
novel mutations all in EXT1 and the genetic defects in four patients. The clinical manifestation and molecular diagnosis allow us
to exclude other similar bone’s diseases and to associate mutations with malignant transformation of the affected tissues. MHE
seems to be in a high frequency in the Argentinean population and the progression in their studies will provide a wider vision of
this pathology in our country and Latin America. CONICET/FONCyT/UCC.
The MHE Research Foundation, we comply with the HONcode standard for health trust worthy information: By the Health On the Net Foundation.
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
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
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.
studying the pathology and genetics of bone tumors.
| This website is regularly reviewed by members of the Scientific and Medical Advisory Board of the MHE Research Foundation. All online submission forms use (SSL AES 256 bit encryption (High); RSA 1024 bit exchange) Protocol with Privacy protection. Our goal is to make this website as safe and user friendly as possible. |
| The MHE Research Foundation is a participating member organization of the United States Bone and Joint Decade, (USBJD) & the USBJD Rare Bone Disease Patient Network |
| Written consent must be obtained to attach web pages or the files attached to this website, please email the webmaster. Email the webmaster: webmaster@mheresearchfoundation.org Materials on this website are protected by copyright Copyright © 2009 The MHE Research Foundation Disclaimer: While many find the information useful, it is in no way a substitute for professional medical care. 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 web page was updated last on 12/16/09, 4:0O pm Eastern time |
The MHE Research Foundation is proud to be an affiliate of the Society For Glycobiology
