Population and Computational Analysis of the MGEA6 P521A Variation as a Risk Factor for Familial Idiopathic Basal Ganglia Calcification (Fahr's Disease)
Population and Computational Analysis of the MGEA6 P521A Variation as a Risk Factor for Familial Idiopathic Basal Ganglia Calcification (Fahr's Disease)
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DOI：
10.1007/s12031-010-9445-7
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发表时间：
2011-03-01
影响因子：
3.1
通讯作者：
Oliveira, Joao R. M.
中科院分区：
文献类型：
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作者：
Lemos, Roberta R.;Oliveira, Danyllo F.;Oliveira, Joao R. M.
家族性特发性基底节钙化，又称Fahr‘s病(FD)，是一种常染色体显性遗传的神经精神障碍，以对称性基底节钙化为特征，偶尔也有其他脑区。目前，有三个基因座与这种毁灭性的疾病有关。第一个(IBGC1)位于14q11.2-21.3，另外两个分别位于2q37(IBGC2)和8p21.1-q11.13(IBGC3)。进一步的研究发现了一种杂合变异(Rs36060072)，该变异存在于位于MGEA6/CTAGE5基因的胞嘧啶变为鸟嘌呤，存在于所有与IBGC1连锁的受影响的美国大家庭中。在美国人群中，这种错义替换导致521位(P521A)的蛋白质结构域中的一个脯氨酸变为丙氨酸，这被认为是一种罕见的变异，其微小等位基因频率(MAF)为0.0058。考虑到给定变异的群体频率是潜在致病性的间接指示，我们在巴西样本的随机对照集中和两个核心家庭中筛选了200条染色体，与我们之前对美国人群的分析进行了比较。此外，我们通过生物信息学程序完成了分析，以预测这种变异的致病性。我们的基因筛查没有发现P521A携带者。将这些数据与之前在美国进行的研究进行比较，我们现在的MAF为0.0036，表明这种突变非常罕见。另一方面，生物信息学分析提供了相互矛盾的发现。目前有多种候选基因和位点可能与FD发病的分子基础有关，其他研究小组提出了与钙代谢相关的2q37和8号染色体(NRG1和SNTG1)基因可能发挥的作用。进一步的诱变和体内研究是必要的，以确认P521A MGEA6变异的致病性。
Familial idiopathic basal ganglia calcification, also known as "Fahr's disease" (FD), is a neuropsychiatric disorder with autosomal dominant pattern of inheritance and characterized by symmetric basal ganglia calcifications and, occasionally, other brain regions. Currently, there are three loci linked to this devastating disease. The first one (IBGC1) is located in 14q11.2-21.3 and the other two have been identified in 2q37 (IBGC2) and 8p21.1-q11.13 (IBGC3). Further studies identified a heterozygous variation (rs36060072) which consists in the change of the cytosine to guanine located at MGEA6/CTAGE5 gene, present in all of the affected large American family linked to IBGC1. This missense substitution, which induces changes of a proline to alanine at the 521 position (P521A), in a proline-rich and highly conserved protein domain was considered a rare variation, with a minor allele frequency (MAF) of 0.0058 at the US population. Considering that the population frequency of a given variation is an indirect indicative of potential pathogenicity, we screened 200 chromosomes in a random control set of Brazilian samples and in two nuclear families, comparing with our previous analysis in a US population. In addition, we accomplished analyses through bioinformatics programs to predict the pathogenicity of such variation. Our genetic screen found no P521A carriers. Polling these data together with the previous study in the USA, we have now a MAF of 0.0036, showing that this mutation is very rare. On the other hand, the bioinformatics analysis provided conflicting findings. There are currently various candidate genes and loci that could be involved with the underlying molecular basis of FD etiology, and other groups suggested the possible role played by genes in 2q37, related to calcium metabolism, and at chromosome 8 (NRG1 and SNTG1). Additional mutagenesis and in vivo studies are necessary to confirm the pathogenicity for variation in the P521A MGEA6.