New Mutations of <i>EXT1</i> and <i>EXT2</i> Genes in German Patients with Multiple Osteochondromas

Heinritz, Wolfram; Hüffmeier, Ulrike; Strenge, Sibylle; Miterski, Bianca; Zweier, Christiane; Leinung, S.; Bohring, Axel; Mitulla, Beate; Peters, Usha; Froster, Ursula G.

doi:10.1111/j.1469-1809.2009.00508.x

Cited by 32 publications

(26 citation statements)

References 42 publications

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“…As previously reported in distinct populations (Ciavarella et al, 2013;Delgado et al,2014;Heinritz et al, 2009;Ishimaru et al, 2016;Pedrini et al, 2005; Sarri on et al, 2013) a high number of novel pathogenic variants was also identified in Brazilian patients. Of all 50 different variants found in this study, 31 (62%) were novel with no description in the Multiple Osteochondroma Mutation Database (MOdb) (http://medgen.ua.ac.be/LOVDDv.2.0/home.php).…”

Section: Discussionsupporting

confidence: 77%

Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas

Santos

Rizzo

Takata

et al. 2018

Molec Gen & Gen Med

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BackgroundMultiple osteochondromas is a dysplasia characterized by growth of two or more osteochondromas. It is genetically heterogeneous, caused by pathogenic variants in EXT1 or EXT2 genes in 70%–90% of patients. The EXT1 is more often mutated than EXT2 gene, with a variable prevalence between populations. There are no data about EXT1 and EXT2 pathogenic variants in patients with multiple osteochondromas in Brazilian population. The aim of this survey is to characterize these to determine the genotype profile of this population.Methods DNA sequencing (Sanger Method) and MLPA analysis were performed to identify point mutations and deletions/duplications in the sample of 153 patients in 114 families.ResultsGermline variants were identified in 83% of families in which EXT2 variants were detected in 46% and EXT1 in 37% of cases. No variants were detected in 17% of them. We identified 50 different variants, 33 (13 frameshift, 11 nonsense, 5 missense, 2 splice site mutation, and 2 large deletions) in EXT1 and 17 (6 frameshift, 6 splice site mutation, 3 nonsense, 1 missense, and 1 large deletion) in EXT2. Of all 50 variants, 31 (62%) were novel, including 20 out of 33 (60,6%) EXT1 and 11 out of 17 (64.7%) EXT2 alleles. The vast majority of variants (88%) were “loss‐of‐function” and two novel hotspots in EXT2 gene were observed in our study.ConclusionThe prevalence of variants detected in the EXT2 gene differs from other researches from Latin America, European, and Asian population. This uncommon prevalence could be related with the newly characterized variant hotspot sites detected in EXT2 gene (p.Ala409Profs*26 and p.Ser290*). A high number of novel variants were also identified indicating that Brazilian population has a unique genetic profile. Characterizing this population and establishing its genotype is essential to understand the molecular pathogenesis of this disease in Brazil.

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Section: Discussionsupporting

confidence: 77%

Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas

Santos

Rizzo

Takata

et al. 2018

Molec Gen & Gen Med

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“…This is further supported by the observation that mutant proteins derived from sequences with missense mutations were completely inactive in vitro (McCormick et al, 1998). Missense mutations are obviously important, as shown not only by the severity of phenotypes in our Family 1, but also by cases and families reported elsewhere (Heinritz et al, 2009).…”

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confidence: 61%

Novel Mutations ofEXT1andEXT2Genes Among Families and Sporadic Cases with Multiple Exostoses

Pei

Wang

Huang

et al. 2010

Genetic Testing and Molecular Biomarkers

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Hereditary multiple exostoses (HME) is an autosomal dominantly inherited disorder characterized by multiple benign cartilage-capped exostoses. Clinical manifestation of the disease is heterogenous. Overriding toes, scoliosis, spinal cord compression, and brachydactyly caused by shortening of metatarsals are rare findings. EXT1 and EXT2 are the genes responsible in most HME patients. We have characterized 11 HME families and 6 sporadic cases involving a total of 37 patients and performed mutational analysis of EXT1 and EXT2. Structural modeling of the wild and mutant proteins was also performed. Thirteen mutations were identified, including 8 that are novel. Among the novel mutations in EXT1, c.1004T>G-associated HME exhibited overriding toes and scoliosis, c.1883+2T>A-associated HME exhibited brachydactyly, and c.459_460delCT-associated exostosis arising from vertebra T4 caused spinal cord compression. Our structural predictions revealed four domains in the proteins encoded by EXT1 and EXT2: signalP, transmembrane regions, exostosin, and glyco_transf-64. The mutations truncated either part or whole of the exostosin domain and/or the C terminus of the glyco_transf-64 domain, or occurred within one of the domains. Our results provide new data for genetic diagnosis, identification of presymptomatic carriers, phenotype-genotype correlation, and understanding of the mechanisms of disease.

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“…Several truncated EXT2s have been predicted to be associated with exostosis and/or HME. Heinritz et al [21] described a mutant transcript in a patient with sporadic exostosis, which probably encoded for a shortened EXT2 protein of 688 amino acids. Wu et al [22] predicted that an aberrant mRNA of EXT2 in a patient with HME would produce a truncated protein of 403 amino acids.…”

Section: Discussionmentioning

confidence: 99%

A Splice Mutation and mRNA Decay of EXT2 Provoke Hereditary Multiple Exostoses

et al. 2014

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BackgroundHereditary multiple exostoses (HME) is an autosomal dominant disease. The classical paradigm of mutation screening seeks to relate alterations in the exostosin glycosyltransferase genes, EXT1 and EXT2, which are responsible for over 70% of HME cases. However, the pathological significance of the majority of these mutations is often unclear.MethodsIn a Chinese family with HME, EXT1 and EXT2 genes were screened by direct sequencing. The consequence of a detected mutant was predicted by in silico analysis and confirmed by mRNA analysis. The EXT1 and EXT2 mRNA and protein levels and the HS patterns in the HME patients were compared with those in healthy controls.ResultsA heterozygous transition (c.743+1G>A) in the EXT2 gene, which co-segregated with the HME phenotype in this family, was identified. The G residue at position +1 in intron 4 of EXT2 was predicted to be a 5′ donor splice site. The mRNA analysis revealed an alternative transcript with a cryptic splice site 5 bp downstream of the wild-type site, which harbored a premature stop codon. However, the predicted truncated protein was not detected by western blot analysis. Decay of the mutant mRNA was shown by clone sequencing and quantification analysis. The corresponding downregulation of the EXT2 mRNA will contribute to the abnormal EXT1/EXT2 ratio and HS pattern that were detected in the patients with HME.ConclusionThe heterozygous mutation c.743+1G>A in the EXT2 gene causes HME as a result of abnormal splicing, mRNA decay, and the resulting haploinsufficiency of EXT2.

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New Mutations of EXT1 and EXT2 Genes in German Patients with Multiple Osteochondromas

Cited by 32 publications

References 42 publications

Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas

Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas

Novel Mutations ofEXT1andEXT2Genes Among Families and Sporadic Cases with Multiple Exostoses

A Splice Mutation and mRNA Decay of EXT2 Provoke Hereditary Multiple Exostoses

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