De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy.
De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy.
复制标题
DOI：
10.1186/s40478-021-01277-5
复制
发表时间：
2021-12-18
影响因子：
7.1
通讯作者：
Yoon G
中科院分区：
文献类型：
--
作者：
Hadjinicolaou A;Ngo KJ;Conway DY;Provias JP;Baker SK;Brady LI;Bennett CL;La Spada AR;Fogel BL;Yoon G
SETX的致病变异导致两种截然不同的神经系统疾病，一种是功能丧失的隐性障碍，一种是共济失调伴动眼运动性失用2型(AOA2)，另一种是显性功能获得运动神经元障碍，即肌萎缩侧索硬化症4型(ALS4)。我们发现两名无血缘关系的患者在SETX基因中有相同的新发现的c.23C >； T(p.Thr8Met)变异，表现为早发性、严重的多发性神经病。由于仅靠DNA序列很难将罕见的私人基因变异与遗传性神经疾病联系起来，我们使用转录网络分析从功能上验证了这些患有严重从头SETX相关神经退行性疾病的患者。加权基因共表达网络分析(WGCNA)被用于从两个不同的ALS4小鼠模型中识别与疾病相关的模块，并与确认的ALS4患者数据进行比较，以获得ALS4特异的转录特征。WGCNA的全血RNA测序数据来自P.Thr8Met SETX变异体，与ALS4和对照组患者进行比较，以确定这一特征是否可用于识别受影响的患者。WGCNA在ALS4小鼠模型数据和ALS4患者数据中发现了重叠的疾病相关模块。小鼠ALS4疾病相关模块与AOA2疾病模块没有关联，证实了不同的疾病特异性特征。携带c.23C >； T(p.Thr8Met)变异的患者的表达谱与人类和小鼠的ALS4特征显著相关，证实了该变异与疾病之间的关系。两名无血缘关系的患者具有相同的P.Thr8Met变异，其相似的临床表现和功能数据提供了强有力的证据，证明P.Thr8Met变异是致病的。这种独特的表型扩大了SETX相关疾病的临床范围。
Pathogenic variants in SETX cause two distinct neurological diseases, a loss-of-function recessive disorder, ataxia with oculomotor apraxia type 2 (AOA2), and a dominant gain-of-function motor neuron disorder, amyotrophic lateral sclerosis type 4 (ALS4). We identified two unrelated patients with the same de novo c.23C > T (p.Thr8Met) variant in SETX presenting with an early-onset, severe polyneuropathy. As rare private gene variation is often difficult to link to genetic neurological disease by DNA sequence alone, we used transcriptional network analysis to functionally validate these patients with severe de novo SETX-related neurodegenerative disorder. Weighted gene co-expression network analysis (WGCNA) was used to identify disease-associated modules from two different ALS4 mouse models and compared to confirmed ALS4 patient data to derive an ALS4-specific transcriptional signature. WGCNA of whole blood RNA-sequencing data from a patient with the p.Thr8Met SETX variant was compared to ALS4 and control patients to determine if this signature could be used to identify affected patients. WGCNA identified overlapping disease-associated modules in ALS4 mouse model data and ALS4 patient data. Mouse ALS4 disease-associated modules were not associated with AOA2 disease modules, confirming distinct disease-specific signatures. The expression profile of a patient carrying the c.23C > T (p.Thr8Met) variant was significantly associated with the human and mouse ALS4 signature, confirming the relationship between this SETX variant and disease. The similar clinical presentations of the two unrelated patients with the same de novo p.Thr8Met variant and the functional data provide strong evidence that the p.Thr8Met variant is pathogenic. The distinct phenotype expands the clinical spectrum of SETX-related disorders.
登录
查看更多内容
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
11.2
作者：
Grunseich C;Patankar A;Amaya J;Watts JA;Li D;Ramirez P;Schindler AB;Fischbeck KH;Cheung VG
通讯作者：
Cheung VG
影响因子：
4.3
作者：
Langfelder P;Luo R;Oldham MC;Horvath S
通讯作者：
Horvath S
影响因子：
--
作者：
Avemaria, Francesca;Lunetta, Christian;Corbo, Massimo
通讯作者：
Corbo, Massimo
影响因子：
1.9
作者：
Gillespie, Meredith K.;Humphreys, Peter;Boycott, Kym M.
通讯作者：
Boycott, Kym M.