Haploinsufficiency of Interferon Regulatory Factor 6 Alters Brain Morphology in the Mouse
Haploinsufficiency of Interferon Regulatory Factor 6 Alters Brain Morphology in the Mouse
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DOI：
10.1002/ajmg.a.36333
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发表时间：
2014-03-01
影响因子：
2
通讯作者：
Nopoulos, Peg
中科院分区：
文献类型：
--
作者：
Aerts, Andrea;DeVolder, Ian;Nopoulos, Peg
口面裂是最常见的出生缺陷之一。在口面裂的许多遗传因素中，干扰素调节因子6（IRF 6）是独特的，因为该基因的突变导致货车德沃德（VWS），这是最常见的裂综合征。此外，IRF 6的变异导致非综合征性唇腭裂（NSCL/P）的风险增加。我们以前的工作表明，VWS或NSCL/P的个体可能有大脑异常（前部较大，后部较小）和小脑较小。本研究的目的是检验以下假设，即破坏小鼠中的Irf 6将导致与患有VWS和NSCL/P的人类报告的那些类似的定量脑变化。（Irf 6（gt 1/+）; n=9）和野生型（Irf 6（+/+）; n=6）年龄相当的小鼠进行4.7-T MRI扫描以获得皮质和皮质下脑结构的定量测量。两组之间的总脑容量无差异。然而，与野生型相比，Irf 6（gt 1/+）小鼠的额叶皮质增大（P=0.028），而后部皮质没有差异。Irf 6（gt 1/+）小鼠小脑体积减小（P=0.004）。Irf 6杂合子小鼠表现出类似的模式，大脑异常先前在人类VWS和NSCL/P。这些结构差异存在于没有明显的口裂。这些结果支持了IRF 6在脑形态测量中的作用，并为口面裂中异常脑发育的潜在遗传联系提供了证据。(c)2013 Wiley Periodicals，Inc.
Orofacial clefts are among the commonest birth defects. Among many genetic contributors to orofacial clefting, Interferon Regulatory Factor 6 (IRF6) is unique since mutations in this gene cause Van der Woude (VWS), the most common clefting syndrome. Furthermore, variants in IRF6 contribute to increased risk for non-syndromic cleft lip and/or palate (NSCL/P). Our previous work shows that individuals with either VWS or NSCL/P may have cerebral anomalies (larger anterior, smaller posterior regions), and a smaller cerebellum. The objective of this study was to test the hypothesis that disrupting Irf6 in the mouse will result in quantitative brain changes similar to those reported for humans with VWS and NSCL/P. Male mice heterozygous for Irf6 (Irf6(gt1/+); n=9) and wild-type (Irf6(+/+); n=6) mice at comparable age underwent a 4.7-T MRI scan to obtain quantitative measures of cortical and subcortical brain structures. There was no difference in total brain volume between groups. However, the frontal cortex was enlarged in the Irf6(gt1/+) mice compared to that of wild types (P=0.028) while the posterior cortex did not differ. In addition, the volume of the cerebellum of Irf6(gt1/+) mice was decreased (P=0.004). Mice that were heterozygous for Irf6 showed a similar pattern of brain anomalies previously reported in humans with VWS and NSCL/P. These structural differences were present in the absence of overt oral clefts. These results support a role for IRF6 in brain morphometry and provide evidence for a potential genetic link to abnormal brain development in orofacial clefting. (c) 2013 Wiley Periodicals, Inc.