Higgins J J, Lombardi R Q, Pucilowska J, Jankovic J, Tan E K, Rooney J P
Center for Human Genetics and Child Neurology, Mid-Hudson Family Health Institute, 279 Main St., Suite 203A, New Paltz, NY 12561, USA.
Neurology. 2005 Feb 8;64(3):417-21. doi: 10.1212/01.WNL.0000153481.30222.38.
Genetic linkage studies have identified two susceptibility loci for essential tremor (ET) on chromosomes 3q13 (ETM1) and 2p24.1 (ETM2). Linkage disequilibrium studies in separate population samples from the United States and Singapore suggest an association between ET and loci at ETM2.
Fine mapping studies were conducted on multiplex and singleton US families linked to ETM2 using newly detected loci within the candidate interval to establish the minimal critical region (MCR) harboring an ET gene. The genes and transcripts within this interval were systematically analyzed by single-strand conformational polymorphism analysis and DNA sequencing.
A 464-kb region between loci D2S2150 and etm1231 was defined as the MCR. The coding regions and flanking intronic splice sites of two genes and seven transcripts in this interval were evaluated for mutations. A missense mutation (828C-->G) in the transcript FLJ14249 (HS1-BP3) was identified in one US family. This mutation was found in another apparently unrelated US family with ET and was absent in 150 control samples (300 chromosomes). The 828C-->G mutation causes a substitution of a glycine for an alanine residue in the HS1-BP3 protein. The HS1-BP3 protein binds to proteins that are highly expressed in motor neurons and Purkinje cells and regulate the Ca2+/calmodulin-dependent protein kinase activation of tyrosine and tryptophan hydroxylase.
A rare variant in the HS1-BP3 gene that is associated with essential tremor (ET) in two families is reported. This finding will facilitate research on the functional role of this gene and related genes in the pathogenesis of ET.
基因连锁研究已在3号染色体q13区域（ETM1）和2号染色体p24.1区域（ETM2）确定了原发性震颤（ET）的两个易感基因座。在美国和新加坡的不同人群样本中进行的连锁不平衡研究表明ET与ETM2位点之间存在关联。
利用候选区间内新检测到的基因座，对与ETM2连锁的美国多病例和单病例家系进行精细定位研究，以确定含有ET基因的最小关键区域（MCR）。通过单链构象多态性分析和DNA测序对该区间内的基因和转录本进行系统分析。
基因座D2S2150和etm1231之间的一个464 kb区域被定义为MCR。对该区间内两个基因和七个转录本的编码区及侧翼内含子剪接位点进行突变评估。在一个美国家系中鉴定出转录本FLJ14249（HS1-BP3）中的一个错义突变（828C→G）。在另一个明显无关的美国家系的ET患者中也发现了该突变，而在150个对照样本（300条染色体）中未发现。828C→G突变导致HS1-BP3蛋白中的一个丙氨酸残基被甘氨酸取代。HS1-BP3蛋白与在运动神经元和浦肯野细胞中高表达的蛋白质结合，并调节酪氨酸和色氨酸羟化酶的钙2+/钙调蛋白依赖性蛋白激酶激活。
报道了HS1-BP3基因中的一种罕见变异，其与两个家系中的原发性震颤（ET）相关。这一发现将有助于研究该基因及相关基因在ET发病机制中的功能作用。
