低髓鞘性脑白质营养不良(HLD)是一种罕见的遗传异质性疾病,可影响中枢神经系统的髓磷脂发育。本研究旨在分析由POLR3A突变引起的HLD-7家族的临床表型和遗传功能。该家庭的先证者(IV6)主要表现为进行性认知能力下降,牙本质发育不良,和低促性腺激素性性腺功能减退。她的三个哥哥(IV1,IV2和IV4)也有不同程度的共济失调,肌张力障碍,或构音障碍,除了上述表现。他们的脑部磁共振成像显示双侧脑室周围白质萎缩,脑萎缩,胼胝体萎缩和变薄。检测到先证者和她的两个活着的兄弟(IV2和IV4)携带POLR3A(NM_007055.4)基因c的纯合突变。2300G>T(p。Cys767Phe),她的近亲已婚父母(III1和III2)是p.Cys767Phe杂合携带者。在构建的POLR3A野生型和p.Cys767Phe突变细胞中,可以看出,野生型POLR3A蛋白的过表达显着增强了5SrRNA和tRNALeu-CAA的PolIII转录。然而,尽管突变型POLR3A蛋白过表达比野生型蛋白过表达增加,未显示预期的PolIII功能进一步增强.相反,PolIII转录功能受挫(POLR3A,BC200和tRNALeu-CAA表达降低),MBP和18SrRNA表达降低。这项研究表明,POLR3Ap.Cys767Phe变体引起突变型POLR3A蛋白的表达增加和PolIII转录本的异常表达,突变型POLR3A蛋白功能异常。
Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.