NF1 Tumor Suppressor Gene Function Narrowing the GAP

tumor suppressor gene, loss of heterozygosity (LOH) or Introduction “second-hit” somatic mutations in the inherited wildTumor suppressor genes are typically identified through type allele have been detected in some tumor types in their association with a familial cancer syndrome. As a NF1 patients (Xu et al., 1992; Legius et al., 1993; Shannon result, information regarding the normal function of the et al., 1994; Colman et al., 1995; Sawada et al., 1996; gene, especially the tissues in which gene function is Serra et al., 1997). However, as will be discussed below, critical, can be inferred from the symptoms of the dissimple haploidy for NF1 function may participate in the ease. Such is the case for NF1, the gene responsible development of many NF1-related symptoms (a phefor neurofibromatosis type I. Patients with NF1 are prenomenon known as haploinsufficiency). An additional disposed to developing a variety of benign and maligcomplexity of the disease is its variable phenotypic exnant tumors, many of which affect the peripheral and pression. Even siblings within the same family can excentral nervous systems (PNS and CNS). However, NF1 hibit a dramatically different range of symptoms, from patients can also exhibit cognitive deficits and develop mild to severe. Thus, so-called modifier genes have other symptoms unrelated to cancer, often affecting been proposed to play an important role in disease manineural crest–derived tissues outside of the PNS, indicatfestation (Riccardi, 1992). ing important growth control and developmental funcThe NF1 gene was cloned in 1990 by the laboratories tions in a wide range of cell and tissue types. Due to of Collins and White (Cawthon et al., 1990; Wallace et al., the prevalence of tumors and other symptoms affecting 1990). The encoded protein, neurofibromin, is expressed the nervous system in NF1, this review will focus on ubiquitously, although its expression is highest in the recent progress in understanding their development usadult PNS and CNS (Upadhyaya and Cooper, 1998). ing molecular genetic, genetic, biochemical, and cell Neurofibromin shares a region of similarity with the catabiological approaches. By considering the findings from lytic domains of the mammalian p120RasGAP protein each of these approaches, an integrated picture regardand an extended similarity with the Saccharomyces cering the normal function of NF1 is beginning to emerge. evisiae Ras-GAP proteins IRA1 and IRA2 (Figure 1) (Bal-