Ellison K A, Fill C P, Terwilliger J, DeGennaro L J, Martin-Gallardo A, Anvret M, Percy A K, Ott J, Zoghbi H
Institute for Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.
Am J Hum Genet. 1992 Feb;50(2):278-87.
Rett syndrome is a neurologic disorder characterized by early normal development followed by regression, acquired deceleration of head growth, autism, ataxia, and stereotypic hand movements. The exclusive occurrence of the syndrome in females and the occurrence of a few familial cases with inheritance through maternal lines suggest that this disorder is most likely secondary to a mutation on the X chromosome. To address this hypothesis and to identify candidate regions for the Rett syndrome gene locus, genotypic analysis was performed in two families with maternally related affected half-sisters by using 63 DNA markers from the X chromosome. Maternal and paternal X chromosomes from the affected sisters were separated in somatic cell hybrids and were examined for concordance/discordance of maternal alleles at the tested loci. Thirty-six markers were informative in at least one of the two families, and 25 markers were informative in both families. Twenty loci were excluded as candidates for the Rett syndrome gene, on the basis of discordance for maternal alleles in the half-sisters. Nineteen of the loci studied were chosen for multipoint linkage analysis because they have been previously genetically mapped using a large number of meioses from reference families. Using the exclusion criterion of a lod score less than -2, we were able to exclude the region between the Duchenne muscular dystrophy locus and the DXS456 locus. This region extends from Xp21.2 to Xq21-q23. The use of the multipoint linkage analysis approach outlined in this study should allow the exclusion of additional regions of the X chromosome as new markers are analyzed. This in turn will result in a defined region of the X chromosome that should be searched for candidate sequences for the Rett syndrome gene in both familial and sporadic cases.
瑞特综合征是一种神经系统疾病，其特征为早期发育正常随后出现退化、头围生长后天性减速、自闭症、共济失调以及刻板的手部动作。该综合征仅在女性中出现，且有少数家族病例通过母系遗传，这表明这种疾病很可能继发于X染色体上的突变。为验证这一假说并确定瑞特综合征基因位点的候选区域，我们利用来自X染色体的63个DNA标记，对两个有母系亲缘关系的患病半姐妹家庭进行了基因型分析。在体细胞杂种中分离出患病姐妹的母源和父源X染色体，并检测所测位点上母源等位基因的一致性/不一致性。36个标记在两个家庭中的至少一个中具有信息性，25个标记在两个家庭中均具有信息性。基于半姐妹中母源等位基因的不一致性，20个位点被排除作为瑞特综合征基因的候选位点。所研究的19个位点被选用于多点连锁分析，因为它们此前已通过参考家系的大量减数分裂进行了基因定位。使用对数优势比分小于-2的排除标准，我们能够排除杜兴肌营养不良症位点和DXS456位点之间的区域。该区域从Xp21.2延伸至Xq21 - q23。随着新标记的分析，采用本研究中概述的多点连锁分析方法应能排除X染色体的其他区域。这反过来将确定X染色体上的一个明确区域，该区域应在家族性和散发性病例中搜索瑞特综合征基因的候选序列。
