GENETIC-LINKAGE BETWEEN VONHIPPEL-LINDAU DISEASE AND 3 MICROSATELLITE POLYMORPHISMS REFINES THE LOCALIZATION OF THE VHL LOCUS
GENETIC-LINKAGE BETWEEN VONHIPPEL-LINDAU DISEASE AND 3 MICROSATELLITE POLYMORPHISMS REFINES THE LOCALIZATION OF THE VHL LOCUS
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DOI：
10.1093/hmg/2.3.279
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发表时间：
1993-03-01
影响因子：
3.5
通讯作者：
FERGUSONSMITH, MA
中科院分区：
文献类型：
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作者：
CROSSEY, PA;MAHER, ER;FERGUSONSMITH, MA
Von Hippel-Lindau (VHL) 病是一种显性遗传的家族性癌症综合征，其特征是视网膜和中枢神经系统血管母细胞瘤、肾细胞癌和嗜铬细胞瘤的发展。 VHL 疾病的基因已定位到染色体 3p25 - p26，并且可以使用连锁 DNA 标记进行症状前诊断。我们之前已将 VHL 疾病基因映射到 D3S1250 和 D3S18 之间 4 cM 的间隔。为了增加症状前诊断的机会并加速分离 VHL 疾病基因的进展，我们尝试通过 29 个家族的遗传连锁分析来鉴定与疾病基因相关的微卫星 DNA 标记。我们发现 VHL 疾病基因与 D3S1038（Zmax = 22.24，theta = 0.01，CI 0.0001 - 0.06）、D3S1110（Zmax = 11.32，theta = 0.07，CI 0.03-0.14）和 D3S651（Zmax = 7.73 于 θ = 0.04，CI 0.008-0.13）。我们将 D3S1038 定位在 D3S1250 和 D3S601 之间，并将 D3S1110 和 D3S651 着丝粒映射到 D3S1250。多点连锁分析绘制了 D3S1038 和 D3S18 之间的 VHL 疾病位点，最大似然位于 D3S601。没有证据表明位点异质性。本研究 (i) 鉴定了 3p25 号染色体上与 VHL 基因相关的三个微卫星 DNA 标记，(ii) 通过定位克隆技术缩小了分离 VHL 疾病基因的目标区域。这些发现将通过提高使用连锁 DNA 标记进行症状前诊断的准确性和可用性来改善 VHL 疾病家庭的管理，并将加速分离 VHL 疾病基因的进展。
Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome characterised by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma and phaeochromocytoma. The gene for VHL disease has been mapped to chromosome 3p25 - p26 and presymtomatic diagnosis using linked DNA markers is available. We have previously mapped the VHL disease gene to a 4 cM interval between D3S1250 and D3S18. To increase access to presymptomatic diagnosis and to accelerate progress towards isolating the VHL disease gene we attempted to identify microsatellite DNA markers linked to the disease gene by genetic linkage analysis in 29 families. We found significant linkage between the VHL disease gene and dinucleotide (CA) repeat polymorphisms at D3S1038 (Zmax = 22.24 at theta = 0.01, CI 0.0001 - 0.06), D3S1110 (Zmax = 11.32 at theta = 0. 07, CI 0.03-0.14) and D3S651 (Zmax = 7.73 at theta = 0.04, CI 0.008-0.13). We localised D3S1038 between D3S1250 and D3S601, and mapped D3S1110 and D3S651 centromeric to D3S1250. Multipoint linkage analysis mapped the VHL disease locus between D3S1038 and D3S18 with the maximum likelihood at D3S601. There was no evidence of locus heterogeneity. This study has (i) identified three microsatellite DNA markers in chromosome 3p25 linked to the VHL gene and (ii) narrowed the target region for the isolation of the VHL disease gene by positional cloning techniques. These findings will improve the management of families with VHL disease by improving the accuracy and availability of presymptomatic diagnosis using linked DNA markers, and will accelerate progress towards isolating the VHL disease gene.