Reproducibility and complications in gene searches: Linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy
Reproducibility and complications in gene searches: Linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy
复制标题
DOI：
10.1086/302763
复制
发表时间：
2000-02-01
影响因子：
9.8
通讯作者：
Dicker, E
中科院分区：
文献类型：
--
作者：
Greenberg, DA;Durner, M;Dicker, E
癫痫的遗传影响的证据是强有力的，但报告确定这些影响冲突的特定染色体起源。一项早期的研究报告说，人类白细胞抗原（HLA）标记物与青少年肌阵挛性癫痫（JME）有遗传联系;这在后来的研究中得到证实。其他报告也发现了与HLA标记的联系。其中一个发现了与15号染色体上的标记连锁的证据，另一个发现了与6号染色体上的标记连锁的证据，着丝粒与HLA连锁。我们通过一名JME患者和整个6号染色体的基因型标记确定了家族。假设男女重组概率相等的连锁分析显示了连锁的证据（LOD评分2.5），但重组分数（θ）较高，表明异质性。当重新进行连锁分析以允许独立的雄性-雌性θ时，在0.5、0.01的雄性-雌性θ下，LOD评分显著更高（4.2）。虽然单用异质性不能解释男女θ的LOD值的总体模式，但JME的异质性和主要的母系遗传可能解释了这一点。通过分析HLA-DP和KLA-DR之间的位点，并根据支持或反对连锁的证据对家系进行分层，我们能够显示JME内异质性的证据，并提出与连锁形式相关的标记。这些数据还表明，JME可能主要是母系遗传，HLA连锁的形式更有可能发生在欧洲血统的家庭。
Evidence for genetic influences in epilepsy is strong, but reports identifying specific chromosomal origins of those influences conflict. One early study reported that human leukocyte antigen (HLA) markers were genetically linked to juvenile myoclonic epilepsy (JME); this was confirmed in a later study. Other reports did trot find linkage to HLA markers. One found evidence of linkage to markers on chromosome 15, another to markers on chromosome 6, centromeric to HLA. We identified families through a patient with JME and genotyped markers throughout chromosome 6. Linkage analysis assuming equal male-female recombination probabilities showed evidence for linkage (LOD score 2.5), but at a high recombination fraction (theta), suggesting heterogeneity. When linkage analysis was redone to allow independent male-female theta s, the LOD score was significantly higher (4.2) at a male-female theta of .5, .01. Although the overall pattern of LOD scores with respect to male-female theta could not he explained solely by heterogeneity, the presence of heterogeneity and predominantly maternal inheritance of JME might explain it. By analyzing loci between HLA-DP and KLA-DR and stratifying the families on the basis of evidence for or against linkage, we were able to show evidence of heterogeneity within JME and to propose a marker associated with the linked form. These data also suggest that JME may be predominantly maternally inherited and that the HLA-linked form is more likely to occur in families of European origin.