Departments of Pediatrics, Neurology and Neurosurgery, Division of Pediatric Neurology, Montreal Children's Hospital, McGill University Heath Center, Montreal, Quebec, Canada.
Am J Hum Genet. 2011 Sep 9;89(3):415-23. doi: 10.1016/j.ajhg.2011.07.014.
Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterized by abnormal white matter visible by brain imaging. It is estimated that at least 30% to 40% of individuals remain without a precise diagnosis despite extensive investigations. We mapped tremor-ataxia with central hypomyelination (TACH) to 10q22.3-23.1 in French-Canadian families and sequenced candidate genes within this interval. Two missense and one insertion mutations in five individuals with TACH were uncovered in POLR3A, which codes for the largest subunit of RNA polymerase III (Pol III). Because these families were mapped to the same locus as leukodystrophy with oligodontia (LO) and presented clinical and radiological overlap with individuals with hypomyelination, hypodontia and hypogonadotropic hypogonadism (4H) syndrome, we sequenced this gene in nine individuals with 4H and eight with LO. In total, 14 recessive mutations were found in 19 individuals with TACH, 4H, or LO, establishing that these leukodystrophies are allelic. No individual was found to carry two nonsense mutations. Immunoblots on 4H fibroblasts and on the autopsied brain of an individual diagnosed with 4H documented a significant decrease in POLR3A levels, and there was a more significant decrease in the cerebral white matter compared to that in the cortex. Pol III has a wide set of target RNA transcripts, including all nuclear-coded tRNA. We hypothesize that the decrease in POLR3A leads to dysregulation of the expression of certain Pol III targets and thereby perturbs cytoplasmic protein synthesis. This type of broad alteration in protein synthesis is predicted to occur in other leukoencephalopathies such as hypomyelinating leukodystrophy-3, caused by mutations in aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1).
脑白质营养不良是一组异质性遗传性神经退行性疾病，其特征是脑成像可见异常的白质。尽管进行了广泛的调查，但据估计，至少有 30%至 40%的个体仍然无法明确诊断。我们将震颤-共济失调伴中央脑白质营养不良（TACH）定位于法裔加拿大家族的 10q22.3-23.1，并对该区间内的候选基因进行测序。在 5 名 TACH 患者中发现了 POLR3A 中的 2 个错义突变和 1 个插入突变，POLR3A 编码 RNA 聚合酶 III（Pol III）的最大亚基。由于这些家族与少齿脑白质营养不良（LO）映射到相同的基因座，并与少脑白质、少牙和促性腺激素低下性性腺功能减退症（4H）综合征的个体具有临床和影像学重叠，我们对 9 名 4H 和 8 名 LO 患者进行了该基因测序。总共在 19 名 TACH、4H 或 LO 患者中发现了 14 个隐性突变，证实这些脑白质营养不良是等位基因。未发现个体携带两个无义突变。4H 成纤维细胞和被诊断为 4H 的个体的尸检大脑的免疫印迹显示 POLR3A 水平显著降低，与大脑皮质相比，大脑白质的降低更为显著。Pol III 有一套广泛的靶 RNA 转录本，包括所有核编码 tRNA。我们假设 POLR3A 的减少导致某些 Pol III 靶标的表达失调，从而扰乱细胞质蛋白合成。这种广泛的蛋白质合成改变预计会发生在其他脑白质病变中，如由于氨酰-tRNA 合成酶复合物相互作用多功能蛋白 1（AIMP1）突变引起的低髓鞘脑白质营养不良-3。
