Higgins Joseph J, Jankovic Joseph, Lombardi Roni Q, Pucilowska Joanna, Tan Eng King, Ashizawa Tetsuo, Ruszczyk Melanie U
Center for Human Genetics and Child Neurology, Mid-Hudson Family Health Institute, 279 Main Street, Suite 203A, New Paltz, NY 12561, USA.
Neurogenetics. 2003 Aug;4(4):185-9. doi: 10.1007/s10048-003-0151-2. Epub 2003 May 22.
The objective of this study was to analyze a sample of unrelated individuals with autosomal dominant essential tremor (ET) for a genetic association with loci in a candidate region (ETM2) on chromosome 2p24.1 that harbors a disease gene for ET. ET is a common movement disorder that is genetically linked to ETM2 in four large families. It is unknown whether this candidate locus is associated with dominantly inherited ET in other individuals. Based on information from previous genetic linkage studies, a linkage disequilibrium study was designed to compare individuals with a family history of ET (n=45) with normal controls (n=70). Three unreported dinucleotide polymorphic loci (etm1240, etm1231, and etm1234) were identified on a physical map of the ETM2 interval in a region of no recombination. The study sample was tested for allele frequency differences by the CLUMP program and haplotypes were analyzed by the FASTEHPLUS program. The allele frequencies were significantly different between ET cases and the control samples for the loci etm1231 (P< or =0.0419) and etm1234 (P<0.0001). A haplotype formed by the loci etm1231 and etm1234 occurred with a frequency of 29% in cases (n=45) and 9% in a white newborn sample (P<0.0001, n=35). The haplotype was not found in normal individuals older than 60 years without tremor (P=0.0063, n=35). This study provides evidence that an ancestral haplotype on chromosome 2p24.1 segregates with the ET disease phenotype in individuals with a family history of the disorder and will facilitate the search for a causative gene.
本研究的目的是分析一组患常染色体显性遗传性特发性震颤（ET）的无关个体样本，以寻找与位于2号染色体2p24.1候选区域（ETM2）中携带ET致病基因的基因座的遗传关联。ET是一种常见的运动障碍，在四个大家族中与ETM2存在遗传联系。目前尚不清楚该候选基因座是否与其他个体的显性遗传性ET相关。基于先前遗传连锁研究的信息，设计了一项连锁不平衡研究，以比较有ET家族史的个体（n = 45）和正常对照（n = 70）。在ETM2区间的物理图谱上，于无重组区域鉴定出三个未报道的二核苷酸多态性基因座（etm1240、etm1231和etm1234）。通过CLUMP程序检测研究样本的等位基因频率差异，并通过FASTEHPLUS程序分析单倍型。对于基因座etm1231（P≤0.0419）和etm1234（P<0.0001），ET病例与对照样本之间的等位基因频率存在显著差异。由基因座etm1231和etm1234形成的单倍型在病例组（n = 45）中的出现频率为29%，在白人新生儿样本（P<0.0001，n = 35）中的出现频率为9%。在无震颤的60岁以上正常个体中未发现该单倍型（P = 0.0063，n = 35）。本研究提供了证据，表明2号染色体2p24.1上的一个祖先单倍型与有该疾病家族史个体的ET疾病表型共分离，这将有助于寻找致病基因。
