RNA聚合酶I转录核糖体DNA以产生前体47SrRNA。这种rRNA的转录后加工产生成熟的28S,18S和5.8SrRNA,形成核糖体,与5SrRNA一起,装配因素,和核糖体蛋白。我们先前报道了RNA聚合酶I催化亚基中的纯合变体,POLR1A,两个兄弟患有脑白质营养不良和进行性病程。然而,疾病机制仍然未知。在这份报告中,我们描述了另一个错义变体POLR1ANM_015425.3:c.1925C>A;p。(Thr642Asn)在两个无关患者中纯合性。患者1为16岁男性,患者2为2岁女性。两名患者都表现出神经功能缺损,脑MRI显示白细胞营养不良减少,和小脑萎缩;在第1例患者中,还伴有斑点低张力和基底神经节小体积。患者1有进行性病程,导致16.5岁时死亡。来自患者1的成纤维细胞的大量体外实验证明,突变的POLR1A导致异常的rRNA加工和降解,核仁稳态异常.蛋白质组学数据分析和进一步的体外实验记录了异常的蛋白质稳态,和内质网应激反应。我们证实POLR1A双等位基因变异会导致神经退行性疾病,扩大对疾病临床表型的认识,并为导致POLR1A相关脑白质营养不良的可能病理机制提供证据。
RNA polymerase I transcribes ribosomal DNA to produce precursor 47S rRNA. Post-transcriptional processing of this rRNA generates mature 28S, 18S and 5.8S rRNAs, which form the ribosomes, together with 5S rRNA, assembly factors and ribosomal proteins. We previously reported a homozygous variant in the catalytic subunit of RNA polymerase I,
POLR1A, in two brothers with leukodystrophy and progressive course. However, the disease mechanism remained unknown. In this report, we describe another missense variant
POLR1A NM_015425.3:c.1925C>A; p.(Thr642Asn) in homozygosity in two unrelated patients. Patient 1 was a 16-year-old male and Patient 2 was a 2-year-old female. Both patients manifested neurological deficits, with brain MRIs showing hypomyelinating leukodystrophy and cerebellar atrophy; and in Patient 1 additionally with hypointensity of globi pallidi and small volume of the basal ganglia. Patient 1 had progressive disease course, leading to death at the age of 16.5 years. Extensive in vitro experiments in fibroblasts from Patient 1 documented that the mutated
POLR1A led to aberrant rRNA processing and degradation, and abnormal nucleolar homeostasis. Proteomics data analyses and further in vitro experiments documented abnormal protein homeostasis, and endoplasmic reticulum stress responses. We confirm that
POLR1A biallelic variants cause neurodegenerative disease, expand the knowledge of the clinical phenotype of the disorder, and provide evidence for possible pathological mechanisms leading to
POLR1A-related leukodystrophy.