de Vries Boukje, Eising Else, Broos Ludo A M, Koelewijn Stephany C, Todorov Boyan, Frants Rune R, Boer Judith M, Ferrari Michel D, Hoen Peter A C 't, van den Maagdenberg Arn M J M
Department of Human Genetics, Leiden University Medical Centre, The Netherlands.
Cephalalgia. 2014 Mar;34(3):174-82. doi: 10.1177/0333102413502736. Epub 2013 Aug 28.
Various CACNA1A missense mutations cause familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of migraine with aura. FHM1 mutation R192Q is associated with pure hemiplegic migraine, whereas the S218L mutation causes hemiplegic migraine, cerebellar ataxia, seizures, and mild head trauma-induced brain edema. Transgenic knock-in (KI) migraine mouse models were generated that carried either the FHM1 R192Q or the S218L mutation and were shown to exhibit increased CaV2.1 channel activity. Here we investigated their cerebellar and caudal cortical transcriptome.
Caudal cortical and cerebellar RNA expression profiles from mutant and wild-type mice were studied using microarrays. Respective brain regions were selected based on their relevance to migraine aura and ataxia. Relevant expression changes were further investigated at RNA and protein level by quantitative polymerase chain reaction (qPCR) and/or immunohistochemistry, respectively.
Expression differences in the cerebellum were most pronounced in S218L mice. Particularly, tyrosine hydroxylase, a marker of delayed cerebellar maturation, appeared strongly upregulated in S218L cerebella. In contrast, only minimal expression differences were observed in the caudal cortex of either mutant mice strain.
Despite pronounced consequences of migraine gene mutations at the neurobiological level, changes in cortical RNA expression in FHM1 migraine mice compared to wild-type are modest. In contrast, pronounced RNA expression changes are seen in the cerebellum of S218L mice and may explain their cerebellar ataxia phenotype.
多种CACNA1A错义突变导致1型家族性偏瘫性偏头痛（FHM1），这是一种罕见的伴有先兆的偏头痛单基因亚型。FHM1突变R192Q与单纯性偏瘫性偏头痛相关，而S218L突变则导致偏瘫性偏头痛、小脑共济失调、癫痫发作以及轻度头部外伤诱发的脑水肿。构建了携带FHM1 R192Q或S218L突变的转基因敲入（KI）偏头痛小鼠模型，结果显示这些模型的CaV2.1通道活性增加。在此，我们研究了它们的小脑和尾侧皮质转录组。
使用微阵列研究突变型和野生型小鼠的尾侧皮质和小脑RNA表达谱。根据它们与偏头痛先兆和共济失调的相关性选择相应的脑区。分别通过定量聚合酶链反应（qPCR）和/或免疫组织化学在RNA和蛋白质水平进一步研究相关的表达变化。
小脑的表达差异在S218L小鼠中最为明显。特别是，酪氨酸羟化酶作为小脑成熟延迟的标志物，在S218L小鼠小脑中明显上调。相比之下，在两种突变小鼠品系的尾侧皮质中仅观察到最小的表达差异。
尽管偏头痛基因突变在神经生物学水平有明显后果，但与野生型相比，FHM1偏头痛小鼠皮质RNA表达的变化较小。相比之下，在S218L小鼠的小脑中观察到明显的RNA表达变化，这可能解释了它们的小脑共济失调表型。
