The Danek Gartner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
J Appl Genet. 2011 Nov;52(4):437-41. doi: 10.1007/s13353-011-0052-2. Epub 2011 May 17.
The purpose of this study was to identify a gene causing non-syndromic X-linked mental retardation in an extended family, taking advantage of the X chromosome inactivation status of the females in order to determine their carrier state. X inactivation in the females was determined with the androgen receptor methylation assay; thereafter, the X chromosome was screened with evenly spaced polymorphic markers. Once initial linkage was identified, the region of interest was saturated with additional markers and the males were added to the analysis. Candidate genes were sequenced. Ten females showed skewed inactivation, while six revealed a normal inactivation pattern. A maximal lod score of 5.54 at θ = 0.00 was obtained with the marker DXS10151. Recombination events mapped the disease gene to a 17.4-Mb interval between the markers DXS10153 and DXS10157. Three candidate genes in the region were sequenced and a previously described missense mutation (P375L) was identified in the ACSL4/FACL4 gene. On the basis of the female X inactivation status, we have mapped and identified the causative mutation in a gene causing non-syndromic X-linked mental retardation.
本研究旨在利用女性的 X 染色体失活状态，鉴定一个导致非综合征性 X 连锁智力低下的基因，以确定其携带者状态。女性的 X 染色体失活状态通过雄激素受体甲基化分析确定；随后，使用均匀间隔的多态性标记物对 X 染色体进行筛查。一旦确定了初步的连锁关系，就用额外的标记物对感兴趣的区域进行饱和处理，并将男性纳入分析。对候选基因进行测序。10 名女性表现出偏性失活，而 6 名女性表现出正常失活模式。标记物 DXS10151 获得最大 lod 评分 5.54（θ=0.00）。重组事件将疾病基因映射到标记物 DXS10153 和 DXS10157 之间 17.4Mb 的区间内。对该区域的三个候选基因进行测序，在 ACSL4/FACL4 基因中发现了一个先前描述的错义突变（P375L）。基于女性的 X 染色体失活状态，我们已经定位并鉴定了导致非综合征性 X 连锁智力低下的基因中的致病突变。
