Gene assignments

Since the previous workshop, 51 characterized genes have been newly assigned or reassigned to the short arm of chromosome 1 (Table 2). The majority of these assignments were made by FISH, although several other methods, including RH and somatic cell hybrid mapping, conventional in situ hybridization, and genetic linkage analysis were also employed. A locus with strong homology to human mitochondrial sequences has been identified at 1p36.3, providing evidence for a recent translocation of the mitochondrial genome to this region (Herrnstadt et al., 1999). Two new, closely linked connexins, GJB3 and GJB5, have been mapped to 1p34-p35, with mutations in GJB3 shown to be causative for erythrokeratodermia variabilis (Richard et al., 1998). Several orthologous genes from other species have been localized to 1p, including homologs of the genes containing the Drosophila mutants patched (PTCH2, 1p32-p34), mago-nashi (MAGOH, 1p33-p34) and disabled (DAB1, 1p31-p32) (Carpenter et al., 1998; Lambert de Rouvroit and Goffinet, 1998; Smyth et al., 1999; Zhao et al., 1998). A number of genes were mapped by characterizing tumor-specific regions of consistent chromosomal rearrangements. These include DAM1 at 1p13.3-p21, amplified in breast cancer cell lines (Nagasaki et al., 1999); AKR7A2 at 1p35-p36.1 in a region deleted in colon carcinomas (Praml et al., 1998); NB4S at 1p22, disrupted by chromosomal translocation in a neuroblastoma (Roberts et al., 1998); and GLCLR at 1p22.1, localized within a region of deletion occurring in mesotheliomas (Rozet et al., 1998). In addition to these gene assignments, a growing number of predicted genes have been identified and mapped through EST and large-scale sequencing projects.

Physical Mapping

Fourteen new contig-based physical maps were reported for 1p in the last year (Table 3). Several of these maps have been produced in collaboration with the Sanger Centre. A high-resolution map surrounding the CDC2L1 locus at 1p36.3 found evidence for duplication of the CDC2L1 and MMP23 genes over a stretch of 100 kb (Gururajan et al., 1998a). Three extensive contigs have been constructed to localize tumor suppressor genes: 2 Mb of 1p35-p36.1 for a colon carcinoma locus (Praml et al., 1998), 1 Mb within 1p32-p33 for a endometrial cancer locus (Arlt et al., 1999), and a 9 Mb stretch of 1p31 in breast carcinoma (Su et al., 1999). A detailed study utilized FISH and large-insert clones to localize chromosomal rearrangements occurring in a newly-defined 1p36 constitutional microdeletion syndrome (Wu et al., 1999).

Five new contig maps of chromosome 1p were presented at the current workshop. Martinsson and co-workers focused on the development of a BAC contig in a 5 cM region on 1p36.2-p36.3 between markers D1S508 and D1S244 to clone genes involved in the genesis of germ cell and neuroblastoma tumors (Martinsson et al., this report). A 5 Mb pulsed field-based physical map of a 1p36.1 region implicated in MYCN-amplified neuroblastomas was presented by Spieker and colleagues (Spieker et al., in press), and a number of genes were ordered within this region. Horii and co-workers (this report) presented a 800 kb BAC contig spanning a constitutional 1p32.2 translocation breakpoint from a neuroblastoma patient. Three overlapping clones harbored the breakpoint, and two transcripts within this region have been identified so far. Lindstrom and co-workers (this report) constructed a PAC contig within 1p36.2 thought to be involved in Charcot-Marie-Tooth disease type 2A. Together with the Sanger Center, they have sequenced and characterized 40 PACs from the region. Brouillard and colleagues (this report) are analyzing a 4-6 cM region on 1p21-p22 involved in cutaneous venous anomalies by physical mapping and the construction of a BAC contig. They have excluded the DR1, TGFBR3 and TFA genes as candidates and are now screening the region for novel genes that may act to regulate angiogenesis.

Gene structures

The genomic structure of 20 genes reported since the previous workshop is summarized in Table 4. Characterization of the genomic structures of several chromosome 1 genes have enabled researchers to determine if gene-specific mutations were present in human diseases. Intragenic mutations in the PTCH2 gene were identified in a single medulloblastoma and basal cell carcinoma (Smyth et al., 1999), suggesting that this gene may act as a tumor suppressor similar to its homolog PTCH on 9q31 which is frequently mutated in basal cell carcinoma (Gailani et al., 1996; Hahn et al., 1996). Similarly, Wong and colleagues identified a deletion within the CDC14A gene in a breast carcinoma cell line (Wong et al., 1999a). However, screening of the CDC42 gene in Schwartz-Jampel syndrome patients failed to reveal mutations at this locus (Nicole et al., 1999). A study by Patskovsky and co-workers determined the genomic structure of GSTM3, one of five identified class mu glutathione transferase genes tightly clustered within 1p13.3 for which genomic structures are known (Patskovsky et al., 1999). Comparison of the five GSTM human and murine genomic structures yielded a remarkable similarity and allowed insights into the evolutionary development of this cluster.