De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy
De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy
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DOI：
10.1016/j.ajhg.2020.12.002
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发表时间：
2021-01-07
影响因子：
9.8
通讯作者：
Yoon, Grace
中科院分区：
文献类型：
--
作者：
Djordjevic, Djurdja;Pinard, Maxime;Yoon, Grace
POLR3B编码RNA聚合酶III的第二大催化亚基，RNA聚合酶III是一种参与转录的酶。POLR3B双等位基因致病变异是低髓素性白质营养不良的公认原因。我们描述了六个POLR3B基因新生错义变异的无关个体，他们的临床表现与POLR3相关的脑白质营养不良有很大不同。这些患者有传入性共济失调、痉挛、不同的智力残疾和癫痫，以及主要的脱髓鞘感觉运动周围神经病。蛋白质建模和蛋白质组学分析揭示了致病的不同机制；从头开始的POLR3B变异导致单个酶亚基的异常结合，而不是影响整个酶的组装或稳定性。我们扩大了与POLR3B致病变异相关的疾病的范围，包括一种与POLR3B相关的从头开始的杂合子疾病。
POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.