Von Recklinghausen neurofibromatosis (NF1) is a common autosomal dominant disorder characterized by abnormalities in multiple tissues derived from the neural crest. No reliable cellular phenotypic marker has been identified, which has hampered direct efforts to identify the gene. The chromosome location of the NF1 gene has been previously mapped genetically to 17q11.2, and data from two NF1 patients with balanced translocations in this region have further narrowed the candidate interval. 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. Previously identified candidate genes, which failed to show abnormalities in NF1 patients, are apparently located within introns of NF1LT, on the antisense strand. A new mutation patient with NF1 has been identified with a de novo 0.5-kilobase insertion in the NF1LT gene. These observations, together with the high spontaneous mutation rate of NF1 (which is consistent with a large locus), suggest that NF1LT represents the elusive NF1 gene.
Linkage analysis of ten Utah kindreds and one Texas kindred with multiple cases of cutaneous malignant melanoma (CMM) provided evidence that a locus for familial melanoma susceptibility is in the chromosomal region 9p13-p22. The genetic markers analyzed reside in a candidate region on chromosome 9p21, previously implicated by the presence of homozygous deletions in melanoma tumors and by the presence of a germline deletion in an individual with eight independent melanomas. Multipoint linkage analysis was performed between the familial melanoma susceptibility locus (MLM) and two short tandem repeat markers, D9S126 and the interferon-alpha (IFNA) gene, which reside in the region of somatic loss in melanoma tumors. An analysis incorporating a partially penetrant dominant melanoma susceptibility locus places MLM near IFNA and D9S126 with a maximum location score of 12.71. Therefore, the region frequently deleted in melanoma tumors on 9p21 presumably contains a locus that plays a critical role in predisposition to familial melanoma.
Genetic studies have implicated the early involvement of a gene on chromosome arm 9p in the development of cutaneous melanoma. We have performed loss-ofheterozygosity studies to confirm these original findings and identify the most frequently rearranged or deleted region of9p.Eight markers were analyzed, including (from 9pter to proximal 9q) D9S33, the (-interferon (IFNBI) locus, the a-interferon (IFNA) gene cluster, D9S126, D9S3, D9S19, the glycoprotein 4(3-galactosylbtansferase (GGTB2) gene, and the argininosuccinate synthetase pseudogene 3 (ASSP3). Two or more of these loci were found to be hemizygously reduced in 12 of 14 (86%) informative metastatic melanoma tumor and cell line DNAs, and homozygous deletions of the marker D9S126 were observed in 2 of 20 (10%) melanoma cell lines. These findings have resulted in the identification of a small critical region of 2-3 megabases on 9p21 in which a putative melanoma tumorsuppressor gene appears likely to reside. Several 9p candidate genes, including IFNBI, the IFNA gene duster, GGTB2, and the tyrosinase-related protein (TYRP) locus, have all been eliminated as potential targets because they are located outside of the homozygously deleted regions.Cytogenetic and molecular studies suggest that several critical genes are important in the progression of cutaneous melanoma (CM) (for review, see ref. 1). One focus is on the p arm of chromosome 9, where four independent reports support the existence of a tumor-suppressor locus which is mutated during the early stages of melanoma tumor development (2-5). Overall, rearrangements of this chromosome occur in nearly half of all melanomas, with the most frequently targeted region extending from 9pter to 9q13 (1). The a-interferon (IFNA) gene cluster and (3-interferon (IFNBI) locus are located within this region and are viewed as potential candidates for involvement in CM because they have growth-inhibitory properties and, as therapeutic agents, have caused the regression of metastatic melanoma (6-8). In addition, interferon-like molecules have been detected in the basal layer of the epidermis, suggesting that they may contribute to the control of normal epidermal growth or regeneration (9).The glycoprotein 4f3-galactosyltransferase (GGTB2) locus and the tyrosinase-related protein (TYRP) gene are also candidates for involvement in CM and reside within this region of 9p. The enzyme encoded by GGTB2 plays a role in glycosylation, and mutations in this protein could adversely affect cell adhesion and/or cell growth (10, 11). This gene has been mapped to 9p13-p21 (6). TYRP is the human homolog of the mouse brown locus (12, 13) and a member of the tyrosinase-related gene family (14). TYRP encodes a transmembrane melanosomal glycoprotein, gp75, which was originally identified in melanoma cells by using autoantibodies from an affected patient (15, 16). The gp75 antigen is expressed exclusively in melanocytic cells (17) and already has an established role in the development of melanoma (18). The TYRP locus was localized init...
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