Two novel mutations in exons 19a and 20 and a BsaI polymorphism in a newly characterized intron of the neurofibromatosis type 1 gene

Klose, Anja; Robinson, Peter N.; Gewies, Andreas; Kaufmann, Dieter; Buske, Annegret; Tinschert, Sigrid; Peters, Hartmut

doi:10.1007/s004390050706

Cited by 8 publications

(1 citation statement)

References 33 publications

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“…The NF1 gene product, neurofibromin, is one of a family of GTPase activating proteins (GAPs) that accelerates the hydrolysis of active Ras-GTP to inactive Ras-GDP (McCormick 1995). Single missense mutations in the GAP-related domain (GRD) of NF1 have been detected in patients (Klose et al 1998). Furthermore, MPNST cell lines and tumors have elevated basal Ras-GTP (Basu et al 1992; DeClue et al 1992; Kim et al 1995; Sherman et al 2000).…”

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confidence: 99%

Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis

et al. 2009

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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas without effective therapeutics. Bioinformatics was used to identify potential therapeutic targets. Paired Box (PAX), Eyes Absent (EYA), Dachsund (DACH), and Sine Oculis (SIX) genes, which form a regulatory interactive network in drosophila, were found to be dysregulated in human MPNST cell lines and solid tumors. We identified a decrease in DACH1 expression, and increases in expression of PAX6, EYA1, EYA2, EYA4, and SIX1- 4. Consistent with the observation that half of MPNSTs develop in neurofibromatosis type 1 patients, subsequent to NF1 mutation, we found that exogenous expression of the NF1-GAP related domain (GRD) normalized DACH1 expression. EYA4 mRNA was elevated more than 100-fold as estimated by quantitative real time PCR in most MPSNT cell lines. In vitro, suppression of EYA4 expression using shRNA reduced cell adhesion and migration and caused cellular necrosis without affecting cell proliferation or apoptotic cell death. MPNST cells expressing sh-EYA4 either failed to form tumors in nude mice or formed very small tumors, with extensive necrosis but similar levels of proliferation and apoptosis as control cells. Our findings identify a role for EYA4 and possibly interacting SIX and DACH proteins in MPNSTs and suggest the EYA4 pathway as a rational therapeutic target.

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confidence: 99%

Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis

et al. 2009

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Analysis of theNF1 gene by temperature gradient gel electrophoresis reveals a high incidence of mutations in exon 4b

et al. 2000

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Preimplantation Genetic Diagnosis for Single Gene Disorders

Fiorentine¹

Practical Preimplantation Genetic Diagnosis

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BACKGROUND:We report on our experience with preimplantation genetic diagnosis (PGD) for single gene disorders (SGDs), from 1999 to 2004, describing strategies and overall clinical outcome of 250 cycles in 174 couples for 23 different genetic conditions. METHODS: PGD cycles included 15 for autosomal dominant, 148 for autosomal recessive and 19 for X-linked SGDs. In addition, 68 cycles of PGD for SGDs were performed in combination with HLA matching. The strategy in each case used an initial multiplex PCR, followed by minisequencing to identify the mutation(s) combined with multiplex PCR for closely linked informative markers to increase accuracy. Linkage analysis, using intragenic and/or extragenic polymorphic microsatellite markers, was performed in cases where the disease-causing mutation(s) was unknown or undetectable. RESULTS: In 250 PGD cycles, a total of 1961 cleavage stage embryos were biopsied. PCR was successful in 3409 out of 3149 (92.4%) biopsied blastomeres and a diagnosis was possible in 1849 (94.3%) embryos. Four hundred and twenty-seven embryos were transferred in 211 cycles, resulting in 71 pregnancies (33.6% per embryo transfer), including 15 biochemical pregnancies, six spontaneous miscarriages, two ectopic pregnancies, which were terminated, and nine pregnancies which are still ongoing. The remaining pregnancies were confirmed to be unaffected and went to term without complications, resulting in the birth of 35 healthy babies. CONCLUSIONS: Minisequencing for mutation detection combined with multiplex fluorescence PCR for linkage analysis is an efficient, accurate and widely applicable strategy for PGD of SGDs. Our experience provides a further demonstration that PGD is an effective clinical tool and a useful option for many couples with a high risk of transmitting a genetic disease.

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Two novel mutations in exons 19a and 20 and a BsaI polymorphism in a newly characterized intron of the neurofibromatosis type 1 gene

Cited by 8 publications

References 33 publications

Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis

Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis

Analysis of theNF1 gene by temperature gradient gel electrophoresis reveals a high incidence of mutations in exon 4b

Preimplantation Genetic Diagnosis for Single Gene Disorders

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