通过单细胞核RNA测序解析的1号染色体镶嵌性获得在一例伴有透明质原浆性星形细胞病的癫痫病例中的细胞类型特异性
Cell-Type Specificity of Mosaic Chromosome 1q Gain Resolved by snRNA-seq in a Case of Epilepsy With Hyaline Protoplasmic Astrocytopathy.
作者信息
Leng Kun, Cadwell Cathryn R, Devine Walter P, Tihan Tarik, Qi Zhongxia, Singhal Nilika S, Glenn Orit A, Kamiya Sherry, Wiita Arun P, Berger Amy C, Shieh Joseph T, Titus Erron W, Paredes Mercedes F, Upadhyay Vaibhav
机构信息
From the Medical Scientist Training Program (K.L., E.W.T.); Department of Pathology (C.R.C., W.P.D., T.T., S.K.); Department of Neurological Surgery (C.R.C.); Weill Institute for Neuroscience (C.R.C., M.F.P.); Department of Laboratory Medicine (Z.Q., A.P.W., E.W.T.); Division of Epilepsy (N.S.S., M.F.P.), Department of Neurology; Department of Radiology and Biomedical Imaging (O.A.G.); Department of Bioengineering and Therapeutic Sciences (A.P.W.), University of California, San Francisco; Chan Zuckerberg Biohub (A.P.W.), San Francisco; Department of Medicine (A.C.B., V.U.), University of California San Francisco; Denali Therapeutics (A.C.B.), South San Francisco; Medical Genetics (J.T.S.), Department of Pediatrics, University of California, San Francisco.
出版信息
Neurol Genet. 2024 Apr 3;10(2):e200142. doi: 10.1212/NXG.0000000000200142. eCollection 2024 Apr.
OBJECTIVES
Mosaic gain of chromosome 1q (chr1q) has been associated with malformation of cortical development (MCD) and epilepsy. Hyaline protoplasmic astrocytopathy (HPA) is a rare neuropathologic finding seen in cases of epilepsy with MCD. The cell-type specificity of mosaic chr1q gain in the brain and the molecular signatures of HPA are unknown.
METHODS
We present the case of a child with pharmacoresistant epilepsy who underwent epileptic focus resections at age 3 and 5 years and was found to have mosaic chr1q gain and HPA. We performed single-nuclei RNA sequencing (snRNA-seq) of brain tissue from the second resection.
RESULTS
snRNA-seq showed increased expression of chr1q genes specifically in subsets of neurons and astrocytes. Differentially expressed genes associated with inferred chr1q gain included and genes associated with cell adhesion or migration. A subpopulation of astrocytes demonstrated marked enrichment for synapse-associated transcripts, possibly linked to the astrocytic inclusions observed in HPA.
DISCUSSION
snRNA-seq may be used to infer the cell-type specificity of mosaic chromosomal copy number changes and identify associated gene expression alterations, which in the case of chr1q gain may involve aberrations in cell migration. Future studies using spatial profiling could yield further insights on the molecular signatures of HPA.
目的
1号染色体长臂（chr1q）的镶嵌性增加与皮质发育畸形（MCD）和癫痫有关。透明原浆性星形细胞病（HPA）是在患有MCD的癫痫病例中发现的一种罕见的神经病理学表现。大脑中chr1q镶嵌性增加的细胞类型特异性以及HPA的分子特征尚不清楚。
方法
我们报告了一名患有药物难治性癫痫的儿童病例，该儿童在3岁和5岁时接受了癫痫病灶切除术，发现存在chr1q镶嵌性增加和HPA。我们对第二次切除的脑组织进行了单核RNA测序（snRNA-seq）。
结果
snRNA-seq显示chr1q基因在神经元和星形胶质细胞亚群中特异性表达增加。与推断的chr1q增加相关的差异表达基因包括与细胞粘附或迁移相关基因。星形胶质细胞亚群显示出与突触相关转录本的显著富集，这可能与在HPA中观察到的星形胶质细胞内含物有关。
讨论
snRNA-seq可用于推断镶嵌性染色体拷贝数变化的细胞类型特异性，并识别相关的基因表达改变，就chr1q增加的情况而言，这可能涉及细胞迁移的异常。未来使用空间分析的研究可能会对HPA的分子特征有进一步的了解。
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