Ulna/Height Ratio as Clinical Parameter Separating EXT1 from EXT2 Families?

Institute of Human Genetics, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.
Genetic Testing (Impact Factor: 1.65). 04/2008; 12(1):129-33. DOI: 10.1089/gte.2007.0070
Source: PubMed


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.

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    • "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. [2001] reported a significant correlation between EXT1 mutations and severe phenotypes in MO patients, more specifically with large numbers of exostoses and short stature. "
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    ABSTRACT: Multiple osteochondromas (MO) is an autosomal dominant skeletal disease characterized by the formation of multiple cartilage-capped bone tumors growing outward from the metaphyses of long tubular bones. MO is genetically heterogeneous, and is associated with mutations in Exostosin-1 (EXT1) or Exostosin-2 (EXT2), both tumor-suppressor genes of the EXT gene family. All members of this multigene family encode glycosyltransferases involved in the adhesion and/or polymerization of heparin sulfate (HS) chains at HS proteoglycans (HSPGs). HSPGs have been shown to play a role in the diffusion of Ihh, thereby regulating chondrocyte proliferation and differentiation. EXT1 is located at 8q24.11–q24.13, and comprises 11 exons, whereas the 16 exon EXT2 is located at 11p12–p11. To date, an EXT1 or EXT2 mutation is detected in 70–95% of affected individuals. EXT1 mutations are detected in ±65% of cases, versus ±35% EXT2 mutations in MO patient cohorts. Inactivating mutations (nonsense, frame shift, and splice-site mutations) represent the majority of MO causing mutations (75–80%). In this article, the clinical aspects and molecular genetics of EXT1 and EXT2 are reviewed together with 895 variants in MO patients. An overview of the reported variants is provided by the online Multiple Osteochondromas Mutation Database ( Hum Mutat 30:1–8, 2009. © 2009 Wiley-Liss, Inc.
    Full-text · Article · Dec 2009 · Human Mutation
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    • "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. "
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    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.
    Full-text · Article · Apr 2009 · Annals of Human Genetics
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    ABSTRACT: To screen for potential mutations in an ethnic Han Chinese family from Shanxi with hereditary multiple exostoses. Polymerase chain reaction and DNA sequencing were used to screen potential mutations in EXT1 and EXT2 genes. For EXT1 gene, two synonymous mutations (P477P and E587E), three intronic mutations (c.1537 -48A>G, c.1721 +203A>G and c.1722 -103C>G) were detected. For EXT2 gene, five intronic mutations (c.-29 -148A>T, c.1080 -18T>A, c.1336 -93C>T, c.1526 -166C>T, and c.1526 -195C>T) were identified. Among these, EXT1 P477P, EXT1 E587E and EXT2 c.1080 -18T>A are polymorphisms listed by Multiple Osteochondroma Mutation Database, whilst the other 7 sites have not been reported. No mutations have been found among all exons of the EXT1 and EXT2 genes in this family. Linkage analysis is necessary for identifying the cause of this disease.
    No preview · Article · Feb 2013 · Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics
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