20 novel point mutations and one large deletion in EXT1 and EXT2 genes: Report of diagnostic screening in a large Italian cohort of patients affected by hereditary multiple exostosis

Ciavarella, Michele; Coco, Michelina; Baorda, Filomena; Stanziale, Pietro; Chetta, Massimiliano; Bisceglia, Luigi; Palumbo, Pietro; Bengala, Mario; Raiteri, Paola; Silengo, Margherita; Caldarini, Camilla; Facchini, R.; Lala, Roberto; Cavaliere, Maria Luigia; Brasi, Davide De; Pasini, Barbara; Zelante, Leopoldo; Guarnieri, Vito; D’Agruma, Leonardo

doi:10.1016/j.gene.2012.11.055

Cited by 28 publications

(34 citation statements)

References 15 publications

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“…The incidence of mutations in this cohort is thus similar to that observed in larger population studies previously (26). Lastly, Ciavarella et al studied a large cohort of HME patients in the southern part of Italy and using a combination of exon sequencing, MLPA and array CGH analyses, they identified 66 mutations and one large EXT2 deletion, amounting to an overall incidence of about 75% (63). Twenty mutations as well as the EXT2 deletion were novel.…”

Section: Spectrum and Roles Of Ext Mutationsmentioning

confidence: 99%

Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments

Pacifici

2017

Curr Osteoporos Rep

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Purpose of review Hereditary Multiple Exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal elements, including long bones, ribs and vertebrae. Due to its intricacies and unresolved issues, HME continues to pose major challenges to both clinicians and biomedical researchers. The purpose of this review is to describe and analyze recent advances in this field and point to possible targets and strategies for future biologically-based therapeutic intervention. Recent findings Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltrasferases responsible for heparan sulfate (HS) synthesis, leading to HS deficiency. Recent genomic inquires have extended those findings, but have yet to provide a definitive genotype-phenotype correlation. Clinical studies emphasize that in addition to the well-known skeletal problems caused by the osteochondromas; HME patients can experience, and suffer from, other symptoms and health complications such as chronic pain and nerve impingement. Laboratory work has produced novel insights into alterations in cellular and molecular mechanisms instigated by HS deficiency and subtending onset and growth of osteochondroma and how such changes could be targeted toward therapeutic ends. Summary HME is a rare and orphan disease and as such, is being studied only by a handful of clinical and basic investigators. Despite this limitation, significant advances have been made in the last few years, and the future bodes well for deciphering more thoroughly its pathogenesis and in turn, identifying a most effective treatment for osteochondroma prevention.

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Section: Spectrum and Roles Of Ext Mutationsmentioning

confidence: 99%

Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments

Pacifici

2017

Curr Osteoporos Rep

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“…One SNP within this region, rs34016643, was shown to have a significant effect on EXT1 promoter activity (the C-allele resulting in a 56% rise in promoter activity) compared to the G-wild-type allele30. The presence of an additional MO-causing gene has been proposed to explain the absence of an EXT1 or EXT2 mutation in a small percentage of MO patients (15–30%)173132. To date, more than 600 different EXT1 and 345 EXT2 mutations have been found worldwide and an update on all reported mutations is deposited at http://medgen.ua.ac.be/LOVD)20.…”

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confidence: 99%

A broad spectrum of genomic changes in latinamerican patients with EXT1/EXT2-CDG

Delgado

Martinez-Domenech

Sarrión

et al. 2014

Sci Rep

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Multiple osteochondromatosis (MO), or EXT1/EXT2-CDG, is an autosomal dominant O-linked glycosylation disorder characterized by the formation of multiple cartilage-capped tumors (osteochondromas). In contrast, solitary osteochondroma (SO) is a non-hereditary condition. EXT1 and EXT2, are tumor suppressor genes that encode glycosyltransferases involved in heparan sulfate elongation. We present the clinical and molecular analysis of 33 unrelated Latin American patients (27 MO and 6 SO). Sixty-three percent of all MO cases presented severe phenotype and two malignant transformations to chondrosarcoma (7%). We found the mutant allele in 78% of MO patients. Ten mutations were novel. The disease-causing mutations remained unknown in 22% of the MO patients and in all SO patients. No second mutational hit was detected in the DNA of the secondary chondrosarcoma from a patient who carried a nonsense EXT1 mutation. Neither EXT1 nor EXT2 protein could be detected in this sample. This is the first Latin American research program on EXT1/EXT2-CDG.

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“…Dependiendo de su número, tamaño y ubicación, pueden causar complicaciones, como deformidad con limitación funcional, compresión de estructuras adyacentes e, incluso, la transformación a condrosarcoma, que puede ocurrir en el 3-5% de los casos. [1][2][3][4] El inicio es variable, desde los 2-3 años hasta los 13-15. Presentan una incidencia estimada que va de 1/18 000 a 1/50 000 casos en los países europeos.…”

Section: A S F O R M a S H E R E D I T A R I A S D E E X O S T O S unclassified

“…5 Son causadas principalmente por mutaciones en genes supresores de tumores, como el EXT1, localizado en 8q24.11, que causa la EMH tipo 1 (OMIM 133700); el EXT2, ubicado en 11p11.2, que causa la EMH tipo 2 (OMIM 133701); y la EMH tipo 3 (OMIM 600209), cuyo locus ha sido localizado en el brazo corto del cromosoma 19 (19p), pero aún no se han detectado alteraciones de este. 1,6,7 Las mutaciones en EXT1 representan entre 56 y 78% Se presenta el caso de una adolescente evaluada de forma multidisciplinaria con diagnóstico clínico, estudio radiológico y molecular de EMH con doble alelo mutante en el gen EXT1 no informado previamente.…”

Section: A S F O R M a S H E R E D I T A R I A S D E E X O S T O S unclassified

Alelo doble mutante en el gen EXT1 no informado previamente en una adolescente con exostosis múltiple hereditaria

et al. 2015

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Presentación de casos clínicos RESUMENLas formas hereditarias de exostosis múltiple, actualmente denominada EXT1/EXT2-CDG dentro de los desórdenes congénitos de la glicosilación, son los tumores óseos benignos más comunes y se caracterizan por la formación de lesiones óseas cubiertas de cartílago, localizadas en yuxtaposición a epífisis de huesos largos, aunque, en los casos graves, pueden presentar una amplia distribución. El inicio es variable desde los 2-3 años hasta los 13-15 y presenta una incidencia estimada que va de 1/18 000 a 1/50 000 casos en los países europeos. Se presenta el caso de un doble alelo mutante en el gen EXT1 no informado previamente en una adolescente y su familia con exostosis múltiple hereditaria. Palabras clave: exostosis múltiple hereditaria, EXT1/EXT2-CDG. ABSTRACTHereditary forms of multiple exostoses, now called EXT1/ EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilagecapped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the Alelo doble mutante en el gen EXT1 no informado previamente en una adolescente con exostosis múltiple hereditaria Double mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostoses disease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18 000 to 1/50 000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses.

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20 novel point mutations and one large deletion in EXT1 and EXT2 genes: Report of diagnostic screening in a large Italian cohort of patients affected by hereditary multiple exostosis

Cited by 28 publications

References 15 publications

Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments

Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments

A broad spectrum of genomic changes in latinamerican patients with EXT1/EXT2-CDG

Alelo doble mutante en el gen EXT1 no informado previamente en una adolescente con exostosis múltiple hereditaria

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