Connor J M, Sampson J
University Department of Medical Genetics, Duncan Guthrie Institute, Yorkhill, Glasgow, UK.
Ann N Y Acad Sci. 1991;615:265-73. doi: 10.1111/j.1749-6632.1991.tb37768.x.
After our initial reports 3-5 supporting a locus for tuberous sclerosis (TSC) on 9q, linkage analysis was undertaken in eight large multigeneration TSC families using nine polymorphic markers. Six of the markers were from the distal long arm of chromosome 9 and three from the long arm of chromosome 11. The data as a whole supported a TSC locus on distal 9q, the peak lod score on multipoint analysis being 3.77 6 cM proximal to the Abelson oncogene locus (ABL). However, analysis of 2-point lod scores using the HOMOG programs revealed significant evidence for genetic heterogeneity (p = 0.01), tight linkage to ABL being highly unlikely in one family. After exclusion of the unlinked family multipoint, analysis gave a peak lod score of 6.1 in the vicinity of ABL. The family unlinked to ABL showed no recombinants with two chromosome 11 probes, but it was too small to provide significant evidence for linkage. Genetic heterogeneity in TSC as demonstrated by this study will complicate efforts to clone the genes by reverse genetics and will severely hamper the use of linked probes for carrier detection and prenatal diagnosis.
在我们最初的3 - 5篇报道支持9号染色体上存在结节性硬化症（TSC）基因座之后，我们利用9个多态性标记对8个大型多代TSC家系进行了连锁分析。其中6个标记来自9号染色体长臂远端，3个来自11号染色体长臂。总体数据支持9号染色体远端存在TSC基因座，多点分析时最高对数优势分数出现在距阿贝尔森致癌基因座（ABL）近端6厘摩处，为3.77。然而，使用HOMOG程序对两点对数优势分数进行分析时发现了显著的遗传异质性证据（p = 0.01），在一个家系中与ABL紧密连锁的可能性极小。排除不连锁的家系后进行多点分析，在ABL附近得到的最高对数优势分数为6.1。与ABL不连锁的家系与两个11号染色体探针均未出现重组，但该家系规模太小，无法提供显著的连锁证据。本研究证明的TSC遗传异质性将使通过反向遗传学克隆基因的工作变得复杂，并将严重阻碍使用连锁探针进行携带者检测和产前诊断。
