Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family.
Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family.
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DOI：
10.3389/fnmol.2015.00085
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发表时间：
2015
影响因子：
4.8
通讯作者：
Harvey RJ
中科院分区：
文献类型：
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作者：
Kalscheuer VM;James VM;Himelright ML;Long P;Oegema R;Jensen C;Bienek M;Hu H;Haas SA;Topf M;Hoogeboom AJ;Harvey K;Walikonis R;Harvey RJ
最近，下一代DNA测序方法加速了神经发育障碍（包括X连锁智力残疾（XLID））中疾病基因的发现。迄今为止，已经鉴定了100多个涉及认知功能的神经元信号通路和网络的人类X染色体基因。尽管取得了这些进展，但大量XLID家族中潜在疾病的突变仍未得到解决。我们报告的决议MRX 78，一个大家庭，6个受影响的男性和7个受影响的女性，显示X连锁遗传。尽管先前的连锁研究已经将该位点定位到X染色体的短臂（Xp11.4-p11.23），但该区域包含太多的候选基因，无法使用常规方法进行分析。然而，我们的X染色体外显子组重测序，生物信息学分析和遗传测试揭示了IQSEC 2中的错义突变（c.C2366T，p.A789V），编码先前与XLID有关的Arf家族GTP酶（ArfGEF）的神经元GDP-GTP交换因子。IQSEC 2的分子模拟显示，A789 V取代导致将较大的侧链插入IQSEC 2的催化Sec 7结构域中的疏水口袋中。预测A789 V变化导致与相邻氨基酸的许多冲突和Sec 7结构域的局部折叠的破坏。与这一发现一致，功能测定揭示重组IQSEC 2A 789 V不能像野生型IQSEC 2那样有效地催化Arf 6上的GDP-GTP交换。总之，这些结果强烈表明IQSEC 2中的A789 V突变是MRX 78家族XLID的根本原因。
Disease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cognitive function have been identified. Despite these advances, the mutations underlying disease in a large number of XLID families remained unresolved. We report the resolution of MRX78, a large family with six affected males and seven affected females, showing X-linked inheritance. Although a previous linkage study had mapped the locus to the short arm of chromosome X (Xp11.4-p11.23), this region contained too many candidate genes to be analyzed using conventional approaches. However, our X-chromosome exome resequencing, bioinformatics analysis and inheritance testing revealed a missense mutation (c.C2366T, p.A789V) in IQSEC2, encoding a neuronal GDP-GTP exchange factor for Arf family GTPases (ArfGEF) previously implicated in XLID. Molecular modeling of IQSEC2 revealed that the A789V substitution results in the insertion of a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain of IQSEC2. The A789V change is predicted to result in numerous clashes with adjacent amino acids and disruption of local folding of the Sec7 domain. Consistent with this finding, functional assays revealed that recombinant IQSEC2A789V was not able to catalyze GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. Taken together, these results strongly suggest that the A789V mutation in IQSEC2 is the underlying cause of XLID in the MRX78 family.