NR2A and NR2B receptor gene variations modify age at onset in Huntington disease
NR2A and NR2B receptor gene variations modify age at onset in Huntington disease
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DOI：
10.1007/s10048-004-0198-8
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发表时间：
2005-02-01
期刊：
影响因子：
2.2
通讯作者：
Epplen, JT
中科院分区：
文献类型：
--
作者：
Arning, L;Kraus, PH;Epplen, JT
已提出N -甲基-D-天冬氨酸（NMDA）受体介导的兴奋性毒性在亨廷顿病（HD）的发病机制中起作用，亨廷顿病是一种常染色体显性遗传疾病，与IT 15基因的5'部分中的一段完美CAG重复序列中的限定扩增相关。CAG重复单位的数量对HD的发病年龄（AO）具有高度预测性。然而，当HD扩增范围在高30 s或低40 s时，AO仅与重复长度适度相关。因此，我们研究了构成NMDA受体（GRIN谷氨酸受体，离子型，N -甲基-D-天冬氨酸）的多聚体复合物的不同亚基的基因是否代表用于调节HD的AO的候选物。在167例HD患者的研究队列中，41至45个CAG单位的重复范围占AO变异的30.8%; 12.3%的额外变异可归因于GRIN 2B基因型变异，4.5%归因于GRIN 2A基因型变异。我们的结论是，这两个基因，编码NR 2B和NR 2A亚型主要在纹状体表达，可能会影响HD的AO的变异。根据这些发现，应重新考虑HD患者和高危人群的神经保护策略。
N -Methyl-D -aspartate (NMDA) receptor-mediated excitotoxicity has been proposed to play a role in the pathogenesis of Huntington disease (HD), an autosomal dominantly inherited disorder associated with defined expansions in a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of CAG repeat units is highly predictive for the age at onset (AO) in HD. However, AO is only modestly correlated with repeat length when the HD expansion range is in the high 30s or low 40s. Therefore, we investigated whether the genes for the different subunits composing the multimeric complexes of NMDA receptors (GRIN glutamate receptor, ionotropic, N -methyl-D -aspartate) represent candidates for modulating the AO of HD. In the studied cohort of 167 HD patients, the repeat range from 41 to 45 CAG units accounted for 30.8% of the variance in AO; 12.3% additional variance could be attributed to GRIN2B genotype variation and 4.5% to GRIN2A genotype variation. We conclude that these two genes, coding for NR2B and NR2A subtypes mainly expressed in the striatum, may influence the variability in AO of HD. Neuroprotective strategies for HD patients and persons at risk should be reconsidered in the light of these findings.