NCI CANCERLIT^® Search: Neurofibromatosis 1 and 2 - September 2001

Last Modified: November 1, 2001

Molecular characterization and gene content of breakpoint boundaries in patients with neurofibromatosis type 1 with 17q11.2 microdeletions.
Bilateral testicular tumour in neurofibromatosis type 1.
Duplication and transposition of the NF1 pseudogene regions on chromosomes 2, 14, and 22.
Identification of duplicated genes in 17q11.2 using FISH on stretched chromosomes and DNA fibers.
NF1 mice: smaller brains but no tumours.
Quantitative effects of Nf1 inactivation on in vivo hematopoiesis.
Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas.

CancerMail from the National Cancer Institute

1
UI - 21375674
AU - Jenne DE; Tinschert S; Reimann H; Lasinger W; Thiel G; Hameister H; Kehrer-Sawatzki H
TI - Molecular characterization and gene content of breakpoint boundaries in patients with neurofibromatosis type 1 with 17q11.2 microdeletions.
SO - Am J Hum Genet 2001 Sep;69(3):516-27
AD - Max-Planck-Institute of Neurobiology, Department of Neuroimmunology, Martinsried, Germany.
Homologous recombination between poorly characterized regions flanking the NF1 locus causes the constitutional loss of approximately 1.5 Mb from 17q11.2 covering > or =11 genes in 5%-20% of patients with neurofibromatosis type 1 (NF1). To elucidate the extent of microheterogeneity at the deletion boundaries, we used single-copy DNA fragments from the extreme ends of the deleted segment to perform FISH on metaphase chromosomes from eight patients with NF1 who had large deletions. In six patients, these probes were deleted, suggesting that breakage and fusions occurred within the adjacent highly homologous sequences. Reexamination of the deleted region revealed two novel functional genes FLJ12735 (AK022797) and KIAA0653-related (WI-12393 and AJ314647), the latter of which is located closest to the distal boundary and is partially duplicated. We defined the complete reading frames for these genes and two expressed-sequence tag (EST) clusters that were reported elsewhere and are associated with the markers SHGC-2390 and WI-9521. Hybrid cell lines carrying only the deleted chromosome 17 were generated from two patients and used to identify the fusion sequences by junction-specific PCRs. The proximal breakpoints were found between positions 125279 and 125479 in one patient and within 4 kb of position 143000 on BAC R-271K11 (AC005562) in three patients, and the distal breakpoints were found at the precise homologous position on R-640N20 (AC023278). The interstitial 17q11.2 microdeletion arises from unequal crossover between two highly homologous WI-12393-derived 60-kb duplicons separated by approximately 1.5 Mb. Since patients with the NF1 large-deletion syndrome have a significantly increased risk of neurofibroma development and mental retardation, hemizygosity for genes from the deleted region around the neurofibromin locus (CYTOR4, FLJ12735, FLJ22729, HSA272195 (centaurin-alpha2), NF1, OMGP, EVI2A, EVI2B, WI-9521, HSA272196, HCA66, KIAA0160, and WI-12393) may contribute to the severe phenotype of these patients.

2
UI - 21078388
AU - Kume H; Tachikawa T; Teramoto S; Isurugi K; Kitamura T
TI - Bilateral testicular tumour in neurofibromatosis type 1.
SO - Lancet 2001 Feb 3;357(9253):395-6

3
UI - 21372079
AU - Luijten M; Redeker S; Minoshima S; Shimizu N; Westerveld A; Hulsebos TJ
TI - Duplication and transposition of the NF1 pseudogene regions on chromosomes 2, 14, and 22.
SO - Hum Genet 2001 Jul;109(1):109-16
AD - Department of Human Genetics, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Numerous NF1 pseudogenes have been identified in the human genome. Those in 2q21, 14q11, and 22q11 form a subset with a similar genomic organization and a high sequence homology. We have studied, by polymerase chain reaction and fluorescence in situ hybridization, the extent of homology of the regions surrounding these NF1 pseudogenes. Our analyses have demonstrated that a fragment of at least 640 kb is homologous between the three regions. Based on previous studies and these new findings, we propose a model for the spreading of the NF1 pseudogene-containing regions. A fragment of approximately 640 kb was first duplicated in chromosome region 2q21 and transposed to 14q11. Subsequently, this fragment was duplicated in 14q11 and transposed to 22q11. A part of the 640-kb fragment in 14q11, with a length of about 430 kb, was further duplicated to a variable extent in 14q11. In addition, we have identified sequences that may facilitate the duplication and transposition of the 640-kb and 430-kb fragments.

4
UI - 21372072
AU - Bentivegna A; Venturin M; Gervasini C; Corrado L; Larizza L; Riva P
TI - Identification of duplicated genes in 17q11.2 using FISH on stretched chromosomes and DNA fibers.
SO - Hum Genet 2001 Jul;109(1):48-54
AD - Department of Biology and Genetics, Medical Faculty, University of Milan, Via Viotti 3/5, 20133 Milan, Italy.
Recent evidence has been provided that links duplicons (REP-P and REP-M) in 17q11.2 flanking the neurofibromatosis type 1 (NF1) gene to the breakpoints of the NF1 microdeletion syndrome. The physical mapping and structural definition of duplicated regions is often impossible by conventional approaches, and so we have used high resolution fluorescence in situ hybridization (FISH) with locus-specific probes of limited size on chromosomes stretched to different degrees to identify novel duplicated genes and expressed sequence tags (ESTs) mapping to 17q11.2. This approach has allowed us to detect and map duplications of the BLMH and GOS28 genes, with one copy lying centromeric and one telomeric to the NF1 gene, and an SHGC30113 transcript with one copy being adjacent and the other distal to the NF1 3' untranslated region. Double-color FISH with a BLMH-specific probe on stretched chromosomes showed that the telomeric BLMH repeat lacked the 5' end of the gene and was 0.8 Mb from its centromeric copy. The distance between the SHGC30113 repeats was estimated as being 500 kb by double-color FISH on highly stretched chromosomes and DNA fibers. The latter approach revealed adjacent SHGC30113-BLMH-specific signals relating to the incomplete BLMH copy. The use of FISH on stretched chromosomes and, where applicable DNA fibers, is a powerful tool for identifying and finely characterizing duplicated regions whose mapping by the classical physical mapping approach is often precluded.

5
UI - 21319678
AU - Hafezparast M
TI - NF1 mice: smaller brains but no tumours.
SO - Trends Mol Med 2001 Jul;7(7):285

6
UI - 21429270
AU - Zhang Y; Taylor BR; Shannon K; Clapp DW
TI - Quantitative effects of Nf1 inactivation on in vivo hematopoiesis.
SO - J Clin Invest 2001 Sep;108(5):709-15
AD - Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
The NF1 tumor-suppressor gene is frequently inactivated in juvenile myelomonocytic leukemia, and Nf1 mutant mice model this myeloproliferative disorder (MPD). Competitive repopulation assays were performed to quantify the proliferative advantage of Nf1(-/-) hematopoietic cells in vivo. Nf1 mutant stem cells demonstrated a growth advantage that was greatest in myeloid lineage cells and least pronounced in T lymphocytes. Surprisingly, although low numbers of Nf1-deficient cells consistently outcompeted wild-type cells, levels of chimerism were stable over months of observation, and MPD was not observed unless threshold numbers of mutant cells were injected. These data showing that normal competitor cells can strongly modulate the growth of mutant populations in vivo have general implications for modeling cancer in the mouse. In particular, strains in which cancer-associated mutations are expressed in fields of target cells may not accurately model early events in tumorigenesis because they eliminate the requirement for a mutant clone to outcompete resident normal cells.

7
UI - 21324756
AU - Serra E; Rosenbaum T; Nadal M; Winner U; Ars E; Estivill X; Lazaro C
TI - Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas.
SO - Nat Genet 2001 Jul;28(3):294-6
AD - Medical and Molecular Genetics Center-IRO, Hospital Duran i Reynals, Autovia de Castelldefels Km 2.7 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Pure populations of neurofibroma-derived Schwann cells bearing both NF1 mutated alleles (NF1-/-) have been isolated from different neurofibromas showing loss of heterozygosity of nearly the entire 17q chromosome. By comparing molecular and fluorescent in situ hybridization analysis of these cells, we demonstrate mitotic recombination is the mechanism underlying this type of loss of heterozygosity leading to reduction to homozygosity of NF1 germline mutation.