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Abstract：
RNA polymerase III-related leukodystrophy (POLR3-related leukodystrophy) is a rare, genetically determined hypomyelinating disease arising from biallelic pathogenic variants in genes encoding subunits of RNA polymerase III (Pol III). Here, we describe the first reported case of POLR3-related leukodystrophy caused by biallelic pathogenic variants in POLR3D, encoding the RPC4 subunit of Pol III. The individual, a female, demonstrated delays in walking and expressive and receptive language as a child and later cognitively plateaued. Additional neurological features included cerebellar signs (e.g., dysarthria, ataxia, and intention tremor) and dysphagia, while non-neurological features included hypodontia, hypogonadotropic hypogonadism, and dysmorphic facial features. Her MRI was notable for diffuse hypomyelination with myelin preservation of early myelinating structures, characteristic of POLR3-related leukodystrophy. Exome sequencing revealed the biallelic variants in POLR3D, a missense variant (c.541C > T, p.P181S) and an intronic splice site variant (c.656-6G > A, p.?). Functional studies of the patient\'s fibroblasts demonstrated significantly decreased RNA-level expression of POLR3D, along with reduced expression of other Pol III subunit genes. Notably, Pol III transcription was also shown to be aberrant, with a significant decrease in 7SK RNA and several distinct tRNA genes analyzed. Affinity purification coupled to mass spectrometry of the POLR3D p.P181S variant showed normal assembly of Pol III subunits yet altered interaction of Pol III with the PAQosome chaperone complex, indicating the missense variant is likely to alter complex maturation. This work identifies biallelic pathogenic variants in POLR3D as a novel genetic cause of POLR3-related leukodystrophy, expanding the molecular spectrum associated with this disease, and proposes altered tRNA homeostasis as a factor in the underlying biology of this hypomyelinating disorder.
摘要：
RNA聚合酶III相关的脑白质营养不良（POLR3相关的脑白质营养不良）是一种罕见的，由编码RNA聚合酶III（PolIII）亚基的基因中的双等位基因致病变体引起的遗传确定的髓鞘减少疾病。这里,我们描述了由POLR3D中的双等位基因致病变体引起的POLR3相关的脑白质营养不良的首例报道，编码PolIII的RPC4亚基。个人，一个女性,小时候表现出走路以及表达和接受语言的延迟，后来认知趋于稳定。其他神经系统特征包括小脑体征（例如，构音障碍,共济失调,和意向震颤)和吞咽困难，而非神经系统的特征包括牙体发育不全,低促性腺激素性性腺功能减退,和畸形的面部特征。她的MRI表现为弥漫性髓鞘减少，早期髓鞘形成结构的髓鞘保留，POLR3相关脑白质营养不良的特征。外显子组测序揭示了POLR3D中的双等位基因变体，一个错觉变体(c.541C>T，p.P181S）和内含子剪接位点变体（c.656-6G>A，p.?)。患者成纤维细胞的功能研究表明POLR3D的RNA水平表达显著降低，以及其他PolIII亚基基因的表达降低。值得注意的是,PolIII转录也被证明是异常的，7SKRNA显着减少，并分析了几种不同的tRNA基因。与POLR3Dp.P181S变体的质谱联用的亲和纯化显示，PolIII亚基的正常组装，但改变了PolIII与PAQosome伴侣复合物的相互作用，表明错义变体可能会改变复杂的成熟。这项工作确定了POLR3D中的双等位基因致病变异作为POLR3相关脑白质营养不良的新遗传原因。扩大与这种疾病相关的分子光谱，并提出了改变的tRNA稳态作为这种髓鞘减少症的潜在生物学因素。
