Molecular Characterization and Gene Content of Breakpoint Boundaries in Patients with Neurofibromatosis Type 1 with 17q11.2 Microdeletions
AUTOR(ES)
Jenne, Dieter E.
FONTE
The American Society of Human Genetics
RESUMO
Homologous recombination between poorly characterized regions flanking the NF1 locus causes the constitutional loss of ∼1.5 Mb from 17q11.2 covering ⩾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 ∼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-α2), NF1, OMGP, EVI2A, EVI2B, WI-9521, HSA272196, HCA66, KIAA0160, and WI-12393) may contribute to the severe phenotype of these patients.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1235482Documentos Relacionados
- A polymorphic cDNA probe on chromosome 17q11.2 located within the NF1 gene [D17S376]
- Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) Contiguous Gene Syndromes by Chromosome Engineering in Mice: Phenotypic Consequences of Gene Dosage Imbalance
- A cytogenetic deletion, del(17)(q11.22q21.1), in a patient with sporadic neurofibromatosis type 1 (NF1) associated with dysmorphism and developmental delay.
- Probable de novo 17q duplication (q11.2-->q21.1): a newly recognised chromosomal syndrome in a child with Klinefelter's syndrome.
- PCR detection of an MboI polymorphism in the ERBB2 (HER2; NEU) gene on chromosome 17q11.2-q12