Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population
Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population
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DOI：
10.1038/sj.mp.4001092
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发表时间：
2002-01-01
影响因子：
11
通讯作者：
Gill, M
中科院分区：
文献类型：
--
作者：
Brophy, K;Hawi, Z;Gill, M
多项证据表明，ADHD是一种多基因疾病，由几个基因相互作用产生，每个基因的作用都很小。突触体相关蛋白25（Synaptosomal-associated protein 25，SNAP-25）是一种在神经细胞中特异性表达的突触前质膜蛋白。该基因编码一种对突触囊泡融合和神经递质释放至关重要的蛋白质。动物模型研究表明，缺损小鼠突变体具有与ADHD相似的多动表型。该模型的过度活跃表型已被证明是SNAP-25基因缺失的结果。SNAP-25基因内或与SNAP-25基因紧密映射的DNA变异可能改变表达水平，因此可能对突触囊泡融合和神经递质释放的功能产生影响。我们使用HHRR和TDT分析了来自爱尔兰的93个ADHD核心家系，发现SNAP-25/Ddel等位基因向ADHD病例的优先传递增加; HHRR（chi（2）= 6.55，P = 0.01）和连锁（TDT）（chi（2）= 6.5，P = 0.015）。与我们的发现相反，巴尔等人（1）报道了Ddel多态性等位基因2的传递增加，尽管这在统计学上并不显著。然而，他们还报告了在他们的加拿大ADHD样本中单倍型（由MnN的等位基因1和Ddel的等位基因2组成）的传播显著增加。目前尚不清楚SNAP-25在ADHD中的作用，直到这些发现在其他ADHD样本中得到证实或反驳。
Several lines of evidence have suggested that ADHD is a polygenic disorder produced by the interaction of several genes each of a minor effect. Synaptosomal-associated protein 25 (SNAP-25) is a presynaptic plasma membrane protein which is expressed highly and specifically in the nerve cells. The gene encodes a protein essential for synaptic vesicle fusion and neurotransmitter release. Animal model studies showed that the coloboma mouse mutant has a hyperactive phenotype similar to that of ADHD. The hyperactive phenotype of this model has been shown to be the result of a deletion of the SNAP-25 gene. DNA variations within or closely mapped to the SNAP-25 gene may alter the level of expression and hence may have an effect on the function of synaptic vesicle fusion and neurotransmitter release. Using HHRR and TDT we analysed 93 ADHD nuclear families from Ireland and found increased preferential transmission of SNAP-25/Ddel allelel to ADHD cases; HHRR (chi(2) = 6.55, P = 0.01) and linkage (TDT) (chi(2) = 6.5, P = 0.015). In contrast to our findings, Barr et al(1) reported an increased transmission of allele 2 of the Ddel polymorphism though this was not statistically significant. However, they also reported a significantly increased transmission of a haplotype (made of allele 1 of MnN and allelle 2 of the Ddel) in their Canadian ADHD sample. It is not clear what the role of SNAP-25 in ADHD is until these findings are either confirmed or refuted in other ADHD samples.