Journal ArticleDOI
Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients.
K. Wimmer,S. Yao,Kathleen Claes,Hildegard Kehrer-Sawatzki,Sigrid Tinschert,T. De Raedt,Eric Legius,Tom Callens,Tom Callens,H. Beiglböck,Ophélia Maertens,Ludwine Messiaen,Ludwine Messiaen +12 more
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TLDR
It was showed that intragenic deletions and/or duplications represent only ∼2% of all NF1 mutations, and MLPA was a useful first step in a comprehensive mutation analysis scheme to quickly pinpoint patients with single‐ or multiexon deletions/duplications as well as patients with a total gene deletion who will not need full sequencing of the complete coding region.Abstract:
Neurofibromatosis type 1 (NF1), the most common tumor-predisposing disorder in humans, is caused by defects in the NF1 tumor-suppressor gene. Comprehensive mutation analysis applying RNA-based techniques complemented with FISH analysis achieves mutation detection rates of � 95% in NF1 patients. The majority of mutations are minor lesions, and � 5% are total gene deletions. We found 13 single- and/or multiexon deletions/duplications out of 1,050 detected mutations using our RNA-based approach in a cohort of 1,100 NF1 patients and confirmed these changes using multiplex ligation-dependent probe amplification (MLPA). With MLPA, we found another 12 novel multiexon deletion/duplications in 55 NF1 patients for whom analysis with multiple assays had not revealed a NF1 mutation, including 50 previously analyzed comprehensively. The extent of the 22 deletions and 3 duplications varied greatly, and there was no clustering of breakpoints. We also evaluated the sensitivity of MLPA in identifying deletions in a mosaic state. Furthermore, we tested whether the MLPA P122 NF1 area assay could distinguish between type I deletions, with breakpoints in low-copy repeats (NF1-LCRs), and type II deletions, caused by aberrant recombination between the JJAZ gene and its pseudogene. Our study showed that intragenic deletions and/or duplications represent only � 2% of all NF1 mutations. Although MLPA did not substantially increase the mutation detection rate in NF1 patients, it was a useful first step in a comprehensive mutation analysis scheme to quickly pinpoint patients with single- or multiexon deletions/duplications as well as patients with a total gene deletion who will not need full sequencing of the complete coding region. V C 2005 Wiley-Liss, Inc.read more
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Journal ArticleDOI
Clinical and genetic aspects of neurofibromatosis 1.
Kimberly Jett,Jan M. Friedman +1 more
TL;DR: One of the most common Mendelian disorders, neurofibromatosis 1, is caused by heterozygous mutations of the NF1 gene and almost one half of all affected individuals have de novo mutations.
Journal ArticleDOI
An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in Exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation
Meena Upadhyaya,Susan M Huson,M. Davies,Nicholas Stuart Tudor Thomas,Nadia Chuzhanova,S. Giovannini,D G R Evans,E. Howard,Bronwyn Kerr,Sian Wyn Griffiths,Claudia Consoli,Lucy Side,Darius J. Adams,Mary Ella M Pierpont,Rachel K. Hachen,A. Barnicoat,Hua Li,P. Wallace,J. P. Van Biervliet,David A. Stevenson,Dave Viskochil,Diana Baralle,Eric Haan,Vincent M. Riccardi,Peter D. Turnpenny,Conxi Lázaro,Ludwine Messiaen +26 more
TL;DR: These data represent results from the first study to correlate a specific small mutation of the NF1 gene to the expression of a particular clinical phenotype, and the biological mechanism that relates this specific mutation to the suppression of cutaneous neurofibroma development is unknown.
Journal ArticleDOI
Elucidating distinct roles for NF1 in melanomagenesis.
Ophélia Maertens,Bryan W. Johnson,Bryan W. Johnson,Pablo E. Hollstein,Pablo E. Hollstein,Dennie T. Frederick,Zachary A. Cooper,Ludwine Messiaen,Roderick T. Bronson,Martin McMahon,Scott R. Granter,Scott R. Granter,Keith T. Flaherty,Jennifer A. Wargo,Richard Marais,Karen Cichowski,Karen Cichowski +16 more
TL;DR: It is shown that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS, and that NF1/neurofibromin inactivation may have an impact on responses to targeted therapies.
Journal ArticleDOI
NF1 Is a Tumor Suppressor in Neuroblastoma that Determines Retinoic Acid Response and Disease Outcome
Michael Hölzel,Sidong Huang,Jan Koster,Ingrid Øra,Arjan Lakeman,Huib N. Caron,Wouter Nijkamp,Jing Xie,Tom Callens,Shahab Asgharzadeh,Robert C. Seeger,Ludwine Messiaen,Rogier Versteeg,René Bernards +13 more
TL;DR: Using a large-scale RNAi genetic screen, crosstalk between the tumor suppressor NF1 and retinoic acid-induced differentiation in neuroblastoma is identified and inhibition of MEK signaling downstream of NF1 restores responsiveness to RA, suggesting a therapeutic strategy to overcome RA resistance in NF1-deficient neuroblastomas.
Journal ArticleDOI
The NF1 somatic mutational landscape in sporadic human cancers
TL;DR: The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1.
References
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Journal ArticleDOI
Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification
Jan P. Schouten,Cathal J. McElgunn,Raymond Waaijer,Danny A. Zwijnenburg,Filip Diepvens,Gerard Pals +5 more
TL;DR: A new method for relative quantification of 40 different DNA sequences in an easy to perform reaction requiring only 20 ng of human DNA is described.
Journal ArticleDOI
Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients
Margaret R. Wallace,Douglas A. Marchuk,Lone B. Andersen,Roxanne Letcher,Hana Odeh,Ann M. Saulino,Jane W. Fountain,Anne Brereton,Jane M. Nicholson,Anna L. Mitchell,Bernard H. Brownstein,Francis S. Collins +11 more
TL;DR: The use of chromosome jumping and yeast artificial chromosome technology has now led to the identification of a large (approximately 13 kilobases) ubiquitously expressed transcript (denoted NF1LT) from this region that is definitely interrupted by one and most likely by both translocations, suggesting that NF1 LT represents the elusive NF1 gene.
Journal ArticleDOI
Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus.
David Viskochil,Arthur M. Buchberg,Gangfeng Xu,Richard M. Cawthon,Jeff Stevens,Roger K Wolff,Melanie Culver,John C. Carey,Neal G. Copeland,Nancy A. Jenkins,Ray White,Peter O'Connell +11 more
TL;DR: These findings strongly suggest that the TBR gene is the NF1 gene, and a number of cDNA clones from the translocation breakpoint region (TBR), one of which hybridizes to an approximately 11 kb mRNA.
Journal ArticleDOI
Neurofibromatosis : phenotype, natural history, and pathogenesis
TL;DR: NF1: historical background and introduction clinical and epidemiologic features evaluation and management genetics molecular biology and pathogenesis neurofibromas and malignanat peripheral nerve sheath tumours cognitive function and academic performance.
Journal ArticleDOI
Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.
Ludwine Messiaen,Tom Callens,Geert Mortier,Diane Beysen,Ina Vandenbroucke,Nadine Van Roy,Frank Speleman,Anne De Paepe +7 more
TL;DR: The data suggest that exons 10a‐10c and 37 are mutation‐rich regions and that together with some recurrent mutations they may account for almost 30% of the mutations in classical NF1 patients, and that it remains possible that a truncated neurofibromin is formed.
Related Papers (5)
An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in Exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation
Meena Upadhyaya,Susan M Huson,M. Davies,Nicholas Stuart Tudor Thomas,Nadia Chuzhanova,S. Giovannini,D G R Evans,E. Howard,Bronwyn Kerr,Sian Wyn Griffiths,Claudia Consoli,Lucy Side,Darius J. Adams,Mary Ella M Pierpont,Rachel K. Hachen,A. Barnicoat,Hua Li,P. Wallace,J. P. Van Biervliet,David A. Stevenson,Dave Viskochil,Diana Baralle,Eric Haan,Vincent M. Riccardi,Peter D. Turnpenny,Conxi Lázaro,Ludwine Messiaen +26 more