Multiple osteochondromas (MO) is an autosomal-dominant inherited disorder. The two genes responsible (EXT1 and EXT2) have been identified. We investigated 12 MO families for phenotype details and the genetic basis by cosegregation and mutation analysis (seven novel pathogenic mutations [five frameshift, one splice site, and one gross deletion] and one novel missense polymorphism). We found EXT1 to be responsible in seven families (19 affected members) and EXT2 in four families (17 affected members). One family remains undetermined. We found a tendency to a more severe phenotype in EXT1 families. As a novel finding, we could identify a single parameter (ulna/height ratio) that separates EXT1 family from EXT2 family in our series.
"Several studies have suggested a more severe phenotype to be associated with EXT1 mutations [Alvarez et al., 2006, 2007; Francannet et al., 2001; Leube et al., 2008; Porter et al., 2004; Wuyts et al., 2005]. Francannet et al.  reported a significant correlation between EXT1 mutations and severe phenotypes in MO patients, more specifically with large numbers of exostoses and short stature. "
"Furthermore, EXT1 was found to be almost exclusively involved in the development of sporadic osteochondromas and chrondrosarcomas (Bovee et al., 1999; Hameetman et al., 2007), but the molecular mechanisms of a secondary malignant transformation still need to be proven. Although, in MO malignant transformation occurs more frequently in EXT1 mutation carriers (Francannet et al., 2001), but chondro-and osteosarcomas were also reported in patients with a mutation in EXT2 (Xiao et al., 2001; Porter et al., 2004; Leube et al., 2008). The 11 exons of the EXT1 gene encode for a protein of 746 amino acids. "
[Show abstract][Hide abstract] ABSTRACT: Mutations in either the EXT1 or EXT2 genes lead to Multiple Osteochondromas (MO), an autosomal dominantly inherited disorder. This is a report on clinical findings and results of molecular analyses of both genes in 23 German patients affected by MO. Mutation screening was performed by using denaturing high performance liquid chromatography (dHPLC) and automated sequencing. In 17 of 23 patients novel pathogenic mutations have been identified; eleven in the EXT1 and six in the EXT2 gene. Five patients were carriers of recurrent mutations in the EXT2 gene (p.Asp227Asn, p.Gln172X, p.Gln258X) and one patient had no detectable mutation. To demonstrate their pathogenic effect on transcription, two complex mutations in EXT1 and EXT2 and three splice site mutations were characterized by mRNA investigations. The results obtained provide evidence for different aberrant splice effects - usage of new cryptic splice sites and exon skipping. Our study extends the mutational spectrum and understanding of pathogenic effects of mutations in EXT1 and EXT2.
Annals of Human Genetics 04/2009; 73(Pt 3):283-91. DOI:10.1111/j.1469-1809.2009.00508.x · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple osteochondromas (MO), an autosomal dominant skeletal disease, is characterized by the presence of multiple cartilage-capped bone tumors (exostoses). Two genes with mutations that are most commonly associated with MO have been identified as EXT1 and EXT2, which are Exostosin-1 and Exostosin-2. In this study, a variety of EXT1 and EXT2 gene mutations were identified in ten Chinese families with MO.
We investigated ten unrelated Chinese families involving a total of 46 patients who exhibited typical features of MO. The coding exons of EXT1 and EXT2 were sequenced after PCR amplification in ten probands. Radiological investigation was conducted simultaneously.
Nine mutations were identified, five in EXT1 and four in EXT2, of which three were de novo mutations and six were novel mutations. One proband carried mutations in both EXT1 and EXT2 simultaneously, and three probands, including one sporadic case and two familial cases, had no detectable mutations.
Our findings are useful for extending the mutational spectrum in EXT1 and EXT2 and understanding the genetic basis of MO in Chinese patients.
Archives of medical research 10/2013; 44(7). DOI:10.1016/j.arcmed.2013.09.008 · 2.65 Impact Factor
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