Genetic analysis of the GRIK2 modifier effect in Huntington's disease.
Genetic analysis of the GRIK2 modifier effect in Huntington's disease.
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DOI：
10.1186/1471-2202-7-62
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发表时间：
2006-09-07
期刊：
影响因子：
2.4
通讯作者：
Gusella JF
中科院分区：
文献类型：
--
作者：
Zeng W;Gillis T;Hakky M;Djoussé L;Myers RH;MacDonald ME;Gusella JF
在亨廷顿氏病（HD）中，神经发病年龄与CAG三核苷酸重复突变的长度呈负相关，但可以被HD基因以外的遗传因素修饰。GRIK2 3'UTR中一个相对不常见的16 TAA等位基因的三核苷酸重复多态性与神经发病年龄早相关，这反映了与GRIK2或邻近基因的功能多态性的连锁不平衡。我们通过对几个个体的所有GRIK2外显子、外显子侧翼序列和3'UTR进行测序来验证这一假设，这些个体对证明修饰子效应至关重要，因为他们显示出比他们的HD CAG突变长度预期的更早的神经发病年龄。虽然检测到10个已知的snp，但在编码或相邻序列中没有发现序列变异，可以解释与16个TAA等位基因的连锁不平衡。利用微卫星、已知snp和在3'UTR中发现的新变异进行的单倍型分析反对这些个体中16个TAA重复等位基因的共同祖先起源。这些数据表明，修饰子效应实际上是由于TAA重复本身，可能通过对GRIK2 mRNA的功能后果。
In Huntington's disease (HD), age at neurological onset is inversely correlated with the length of the CAG trinucleotide repeat mutation, but can be modified by genetic factors beyond the HD gene. Association of a relatively infrequent 16 TAA allele of a trinucleotide repeat polymorphism in the GRIK2 3'UTR with earlier than expected age at neurological onset has been suggested to reflect linkage disequilibrium with a functional polymorphism in GRIK2 or an adjacent gene. We have tested this hypothesis by sequencing all GRIK2 exons, the exon-flanking sequences and 3'UTR in several individuals who were crucial to demonstrating the modifier effect, as they showed much earlier age at neurological onset than would be expected from the length of their HD CAG mutation. Though ten known SNPs were detected, no sequence variants were found in coding or adjacent sequence that could explain the modifier effect by linkage disequilibrium with the 16 TAA allele. Haplotype analysis using microsatellites, known SNPs and new variants discovered in the 3'UTR argues against a common ancestral origin for the 16 TAA repeat alleles in these individuals. These data suggest that the modifier effect is actually due to the TAA repeat itself, possibly via a functional consequence on the GRIK2 mRNA.
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影响因子：
5.8
作者：
Mayor, C;Brudno, M;Dubchak, I
通讯作者：
Dubchak, I
影响因子：
2.5
作者：
Howe, JR
通讯作者：
Howe, JR
DOI：
10.1002/ajmg.1320180115
发表时间：
1984-01-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
FARRER, LA;CONNEALLY, PM;YU, P
通讯作者：
YU, P
DOI：
10.1073/pnas.041566798
发表时间：
2001-02-13
影响因子：
11.1
作者：
Holbert, S;Denghien, I;Néri, C
通讯作者：
Néri, C
影响因子：
2.5
作者：
Chattopadhyay, B;Ghosh, S;Bhattacharyya, NP
通讯作者：
Bhattacharyya, NP