Gene/Protein Disease Symptom Drug Enzyme Compound
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Multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited cancers that have in common the clinical feature of medullary thyroid carcinoma (MTC). We have performed both genomic long-range restriction mapping and yeast artificial chromosome (YAC) contig assembly and restriction mapping to establish physical linkage, order, and distances between six loci in 10q11.2 near the genes responsible for these hereditary cancers. RET, D10S94, D10S182, and D10S102 have been mapped in genomic DNA. RET, D10S94, D10S182, D10F38S3, and the 10q11.2 sequences detected by DNA marker DM124 are encompassed by a 1-Mb YAC contig. Six physically linked loci are within 1.4 Mb and have an order and orientation of 10cen, D10F38S3, DM124, RET, D10S94, D10S182, D10S102, 10qter. Mutations in the RET proto-oncogene have recently been demonstrated to be associated with MEN 2A and FMTC. RET is located within a genetically defined MEN2A candidate interval between D10S141 and D10S94; MEN2B has been mapped to a larger, overlapping region between D10S141 and a more distal locus, RBP3. Both our genomic physical map and our YAC contig span the entire MEN2A candidate region and overlap with that of MEN2B. These maps will facilitate the identification of genes that can be considered candidates for MEN2B and the identification of tumor-specific alterations important in sporadic MTC.
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PMID:Genomic and yeast artificial chromosome long-range physical maps linking six loci in 10q11.2 and spanning the multiple endocrine neoplasia type 2A (MEN2A) region. 790 24

An overlapping set of 21 yeast artificial chromosomes (YACs) spanning the RET proto-oncogene [Takahashi et al., Oncogene 3 (1988) 571-578] and D10S102 markers on human chromosome 10 was isolated in a series of hybridization-based chromosomal walks in a YAC library. Genetic linkage analyses implicate this chromosomal region as the location of the gene (MEN2A) responsible for multiple endocrine neoplasia type 2A. Four YACs carrying a RET sequence-tagged site (STS) and two YACs carrying a D10S102 STS were used to initiate chromosome walks. These were based on hybridization of Alu element-mediated polymerase chain reaction (Alu-PCR) products from YACs to dot blots of Alu-PCR products from complex pools of YAC clones. The hybridization anchor content of YACs identified in the walks was confirmed by probing blots of Alu-PCR products from individual YACs and by comparing Alu-PCR fingerprints of each YAC. Ten hybridization-based Alu-PCR anchors and three STS anchors were ordered within eleven intervals created by the 21 overlapping YACs. The order of anchors requiring the fewest gaps in the YACs is consistent with the walking results and establishes the STS anchor order as D10S102-D10S94-RET. The overlapping set of YACs represents about 1.55 Mb of the human genome according to restriction mapping of four representative YACs in the contig. These results demonstrate the power of Alu-PCR hybridization for chromosomal walking and provide a rich source of overlapping YACs which can be used to identify candidate MEN2A genes.
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PMID:Rapid identification of overlapping YACs in the MEN2 region of human chromosome 10 by hybridization with Alu element-mediated PCR products. 790 72

The genetic loci RET, D10S94, and D10S102 from human chromosome 10q11.2 are very closely linked to a locus responsible for the multiple endocrine neoplasia type 2 (MEN2A and MEN2B) and medullary thyroid carcinoma (MTC1) familial cancer syndromes. We have constructed a 1.5-megabase contig consisting of six genomic yeast artificial chromosome clones which include these loci and define their physical order. A critical crossover event has been identified within the map interval; this event places the MEN2A locus centromeric to D10S102 and defines the orientation of the physical map on the chromosome. The orientation of the contig and order of the markers are centromere-RET-D10S94-D10S102-telomere. In addition, a microsatellite repeat polymorphism with a heterozygosity of 71% at the RET locus and a restriction fragment length polymorphism with a heterozygosity of 42% detected by a lambda clone from the D10S94 locus have been developed for high-resolution genetic linkage mapping and predictive diagnostic testing. These data place three important markers on a contiguous physical map, narrow the MEN2 disease locus interval, and provide a framework for further candidate gene identification efforts. Placement of these genetic loci along a clone-based map and continued expansion of the contig will also facilitate efforts to determine the relationship of physical to genetic distance near the centromeres of human chromosomes.
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PMID:A 1.5-megabase yeast artificial chromosome contig from human chromosome 10q11.2 connecting three genetic loci (RET, D10S94, and D10S102) closely linked to the MEN2A locus. 809 42