To expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.

We performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [¹H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts.

The patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in POLR3A, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant.

Mutations in the POLR3A gene cause POLR3A-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of POLR3A-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate.

通过评估错义和剪接受体突变的功能后果来扩展POLR3A突变的临床表型。

我们对一名患有严重全身性肌张力障碍、代谢性酸中毒、白细胞增多、肌张力减退和吞咽困难的 9 岁女性患者进行了全外显子组测序，以确定可能的致病突变。^{脑部 MRI 通过 [ 1} H]-磁共振波谱显示基底节萎缩和存在乳酸和脂质峰。通过定量实时 (qRT)-PCR 测量 Pol III 靶基因的表达水平，以研究患者成纤维细胞中双等位基因突变的致病性。

该患者是新错义 c.3721G>A (p.Val1241Met) 和剪接区 c.1771-6C>G 突变的复合杂合子POLR3A，该基因编码 RNA 聚合酶 III (Pol III) 的催化亚基. 对于 c.1771-6C>G 突变，观察到异常剪接。在患者成纤维细胞中观察到 Pol III 靶标（HNRNPH2、泛素 B、乳转铁蛋白和 HSP90AA1）的 RNA 表达水平降低，野生型蛋白过表达但 p.Val1241Met 变体未恢复至正常水平。

POLR3A基因的突变导致POLR3A相关的髓鞘性白质营养不良，伴有或不伴有少牙症或促性腺功能减退症 (HLD7, OMIM: 607694) 和新生儿早衰综合征 (OMIM: 264090)，两者均具有高表型变异性。我们证明了 c.1771-6C>G 和 c.3721G>A 突变导致早发性疾病的致病性。我们患者的表型扩展了POLR3A相关突变的临床表现，并提出了一种新的分类，我们建议将其命名为具有退化、异常运动和乳酸增加的神经发育障碍。