Gelernter J, Kennedy J L, van Tol H H, Civelli O, Kidd K K
Yale University School of Medicine, New Haven, Connecticut.
Genomics. 1992 May;13(1):208-10. doi: 10.1016/0888-7543(92)90222-e.
Dopaminergic pathophysiology is important in several psychiatric illnesses. The recently cloned D4 dopamine receptor gene (DRD4) shows considerable homology to the D2 and D3 dopamine receptors (DRD2 and DRD3); pharmacologically, its affinity for the atypical antipsychotic clozapine is much higher than that of these other dopamine receptors. Probe pB28 for this locus recognizes an informative HincII polymorphism. We typed this polymorphism on several large reference families (a total of about 271 individuals) to place DRD4 in the genetic linkage map. Pairwise linkage analysis (using ILINK) provided evidence for close linkage to the distal 11p loci tyrosine hydroxylase (TH) and the Harvey ras oncogene (HRAS). We used our version of LINKMAP adapted to run under distributed parallel processing (Linda-LINKMAP) for an analysis moving DRD4 across a fixed map with HRAS set 3.8 cM distal to TH. This localized DRD4 close to HRAS, with no crossovers observed between those loci and a maximum lod score of 19.9 (2 cM distal to HRAS). The one LOD unit support interval extends from about 1 cM proximal to HRAS to 8 cM distal to HRAS. Crossovers identified in one kindred place DRD4 distal to TH, providing further evidence for its location close to HRAS, making DRD4 one of the most telomeric of 11p markers. (This also places DRD4 in band 11p15.5.)
多巴胺能病理生理学在几种精神疾病中具有重要意义。最近克隆的D4多巴胺受体基因（DRD4）与D2和D3多巴胺受体（DRD2和DRD3）显示出相当的同源性；在药理学上，它对非典型抗精神病药物氯氮平的亲和力远高于其他多巴胺受体。该基因座的探针pB28识别一种信息丰富的HincII多态性。我们在几个大型参考家系（总共约271人）中对这种多态性进行分型，以便将DRD4定位到遗传连锁图谱中。成对连锁分析（使用ILINK）提供了与11p远端位点酪氨酸羟化酶（TH）和哈维ras癌基因（HRAS）紧密连锁的证据。我们使用经过改编可在分布式并行处理（Linda-LINKMAP）下运行的LINKMAP版本，进行将DRD4在固定图谱上移动的分析，其中HRAS设定在TH远端3.8 cM处。这将DRD4定位在靠近HRAS的位置，在这些位点之间未观察到交叉，最大lod分数为19.9（在HRAS远端2 cM处）。一个lod单位支持区间从HRAS近端约1 cM延伸到HRAS远端8 cM。在一个家系中鉴定出的交叉将DRD4定位在TH远端，为其靠近HRAS的位置提供了进一步证据，使DRD4成为11p标记中最末端的标记之一。（这也将DRD4定位在11p15.5带中。）
