The Genetic Institute, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel.
Neurogenetics. 2011 Nov;12(4):325-32. doi: 10.1007/s10048-011-0293-6. Epub 2011 Aug 12.
A strong association was established between the GBA gene and Parkinson's disease (PD) worldwide. The most frequent GBA mutation among the Ashkenazi population (p.N370S) was previously associated with the c.1051T>C (p.F351L) alteration in the closely located MTX1 gene. We further studied the association between these two genes and its possible effect on PD. The entire coding region and exon-intron boundaries of MTX1 were analyzed in 81 PD patient carriers of GBA mutations, 15 healthy controls that carry GBA mutations, and in 25 non-carrier patients. Among them, the MTX1 c.184T>A (p.S63T) variation was detected in 93% of GBA mutation carriers (both patients and healthy controls) and in 64% of non-carrier patients (p = 0.0008). This alteration was analyzed in 600 consecutively recruited Ashkenazi PD patients and in 353 controls, all genotyped for the LRRK2 p.G2019S and GBA founder mutations. A significantly higher frequency of the MTX1 c.184A allele was found in carriers of GBA mutations compared to non-carriers (0.67 and 0.45, respectively, p < 0.0001). The homozygous MTX1 c.184A/A genotype was associated with a significantly earlier age of motor symptoms onset in patients with GBA mutations compared to other groups of patients tested (5.1-5.9 years younger, p = 0.002-0.01). A significantly higher frequency of early-onset PD (<50 years) was detected among patients carrying both GBA mutation and the homozygous MTX1 c.184A/A genotype (35.9%, compared to 13.6-17.5%, p = 0.028). Our results raise the possibility that alteration on the opposite allele, which is in trans to the GBA mutant allele, may affect the clinical course of GBA-associated PD.
GBA 基因与帕金森病（PD）之间存在很强的关联。在阿什肯纳兹人群中最常见的 GBA 突变（p.N370S）之前与紧密相邻的 MTX1 基因中的 c.1051T>C（p.F351L）改变有关。我们进一步研究了这两个基因之间的关联及其对 PD 的可能影响。在 81 名携带 GBA 突变的 PD 患者、15 名携带 GBA 突变的健康对照者和 25 名非携带者患者中，分析了 MTX1 的整个编码区和外显子-内含子边界。在 93%的 GBA 突变携带者（患者和健康对照者）和 64%的非携带者患者中检测到 MTX1 c.184T>A（p.S63T）变异（p=0.0008）。在 600 名连续招募的阿什肯纳兹 PD 患者和 353 名对照者中分析了该改变，所有患者均为 LRRK2 p.G2019S 和 GBA 创始人突变的基因分型。携带 GBA 突变的患者中 MTX1 c.184A 等位基因的频率明显高于非携带者（分别为 0.67 和 0.45，p<0.0001）。与其他测试的患者组相比，携带 GBA 突变的患者中 MTX1 c.184A/A 纯合基因型的患者的运动症状发病年龄明显更早（年轻 5.1-5.9 岁，p=0.002-0.01）。携带 GBA 突变和 MTX1 c.184A/A 纯合基因型的患者中，早发性 PD（<50 岁）的频率明显更高（35.9%，而 13.6-17.5%，p=0.028）。我们的研究结果提出了这样一种可能性，即与 GBA 突变等位基因相反的等位基因的改变可能会影响 GBA 相关 PD 的临床过程。
