Genetic and physical map of the von Recklinghausen neurofibromatosis (NF1) region on chromosome 17.

Abstract

The von Recklinghausen neurofibromatosis 1 (NFI) locus has been previously assigned to the proximal long arm of chromosome 17, and two NF1 patients have been identified who have constitutional balanced translocations involving 17q11.2. We have constructed a cosmid library from a chromosome-mediated gene transfectant, KLTS, that contains approximately 10% of chromosome 17, including 17q11.2. Cosmids isolated from this library have been mapped across a panel of somatic cell hybrids, including the hybrids from the two patients, and have been localized to seven small regions of proximal 17q. We have 5 cosmids that map directly above the two NFI translocations, and 11 cosmids that map directly below. Of these, 2 cosmids in each region are linked to the disease locus and 3 of these cosmids show no recombination.One distal cosmid, 2B/B35, detects the two NFI translocations by pulsed-field gel analysis and has been used to produce a long-range restriction map that covers the translocations.Von Recklinghausen neurofibromatosis 1 (NF1) is one of the most common dominantly inherited disorders in man with an estimated frequency of 1/3000 and a high proportion of new mutations, estimated between 30 and 50%o (1). Its expression is extremely variable, even within affected families, and ranges from minor skin manifestations (e.g., cafe-au-lait spots) to severely disabling and sometimes lethal neurological tumors. Linkage of this disorder to markers on proximal 17q has been demonstrated (2, 3) and linked flanking markers have been defined (4, 5). As with several other dominantly inherited tumor-forming syndromes (e.g., retinoblastoma or adenomatous polyposis coli), it seemed likely that NF1 might be the result of mutations in a tumor-suppressor gene. However, there are as yet no reports of loss of heterozygosity in NF1 for markers close to the NFI locus.The finding of two individuals with NF1 carrying different constitutional balanced reciprocal translocations with breaks at 17q11.2 (6, 7) strongly suggested that the region of these translocations would contain the NFI gene. Probes that map close to the translocations have been used to make long-range maps of this region (8,9). By using a chromosome-mediated gene transfectant (CMGT), KLT8, containing about 10% of chromosome 17, including the NFl region (10), we have isolated cosmids flanking the NFI translocations. Restriction fragment length polymorphisms (RFLPs) in these cosmids have allowed us to map them by genetic linkage. Our closest probe lies distal to the translocations and has no recombinants with NFI. It contains a CpG-rich island and has been used by analysis of pulsed-field gel electrophoresis (PFGE) results to define a long-range restriction map covering the translocations that differ from the published maps (27). In this paper we present the genetic linkage data on our flanking probes and our physical map of the translocation region. MATERIALS AND METHODSCell Lines. KLT8, PLT6B, and PLT8 are CMGTs containing fragments of chromosome 17 (10). PCTBA1.8 (11) i...

Loss of NF1 alleles in phaeochromocytomas from patients with type 1 neurofibromatosis

“…All of these markers lie within a region of about 15 centimorgans on the linkage map, flanking the NFI locus (Goldgar et al. 1988;Yagle et al 1990). AE 25 is a cDNA from the NFI gene .…”

Research Update and Recent Developments in the Management of Scoliosis in Neurofibromatosis Type 1

“…21,22 The gene was successfully cloned in 1990. [23][24][25][26][27] The full length of NF-1 gene is 350 kb containing 60 exons on chromosome 17q11.2. [28][29][30] The NF-1 gene encodes a protein called neurofi bromin, which is a tumorsuppressor gene expressed in several tissues and organs.…”

Complete physical map and gene content of the human NF1 tumor suppressor region in human and mouse

“…According to their observations, the NF1 gene is not only surrounded by duplicons derived from the WI‐12393 ( KIAA0563 ‐related) gene at a distance of 400 and 700 kb on each side, but also might be organized as a highly homologous tandem repeat within 17q11.2. We were puzzled by these findings, given that NF1 ‐related sequences adjacent to the bona fide NF1 gene at 17q11.2 have not been detected in previous PCR and microsatellite analyses (Jorde et al, 1993; Messiaen et al, 1993; Li et al, 1995; Purandare et al, 1996; Valero et al, 1996), physical mapping studies (Fountain et al, 1989a, b; Ledbetter et al, 1989; Yagle et al, 1990), or cytogenetic studies of constitutional translocations such as the t(17;22) (q11.2q11.2), which disrupts the NF1 gene in intron 31 (Kehrer‐Sawatzki et al, 1997b, 2002).…”