Retinal Vasculopathy With Cerebral Leukodystrophy: Clinicopathologic Features of an Autopsied Patient With a Heterozygous TREX 1 Mutation
Retinal Vasculopathy With Cerebral Leukodystrophy: Clinicopathologic Features of an Autopsied Patient With a Heterozygous TREX 1 Mutation
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DOI：
10.1093/jnen/nly115
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发表时间：
2019-02-01
影响因子：
3.2
通讯作者：
Kakita, Akiyoshi
中科院分区：
文献类型：
--
作者：
Saito, Rie;Nozaki, Hiroaki;Kakita, Akiyoshi
视网膜血管病变伴脑白质营养不良（RVCL）是一种常染色体显性遗传疾病，由于TREX1基因的移码突变，累及大脑、视网膜、肾脏和其他全身微血管。在生理条件下，TREX1蛋白定位于细胞质和核周区域，但响应于氧化DNA损伤而易位到细胞核中。据推测，蛋白质的异常定位可能与RVCL患者的全身性微血管病变有关。然而，RVCL患者大脑和内脏器官中TREX 1的细胞表达尚不清楚。在这里，我们报告的临床病理特征的尸检患者与杂合子T249fs突变TREX1。患者表现出血管病变的临床表型，伴有视网膜病变、肾病和卒中。增强CT显示皮质下白色物质中的肿瘤性病变。在组织学上，病变由融合性坏死灶组成，伴钙化和小血管壁纤维增厚。TREX 1免疫组化结果显示，在中枢神经系统和内脏器官的细胞核中呈阳性，表明截短蛋白的异常定位，并且在病变内的少突胶质细胞中表达显著，表明该蛋白可能参与了导致白色物质变性的血管病变的病理机制。
Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an autosomal-dominant disorder involving the cerebral, retinal, renal, and other systemic microvessels due to frameshift mutations in the TREX1 gene. Under physiological conditions, the TREX1 protein is localized in the cellular cytoplasm and perinuclear area, but translocates into the nucleus in response to oxidative DNA damage. It has been speculated that aberrant localization of the protein may be associated with systemic microangiopathy in patients with RVCL. However, cellular expression of TREX1 in the brain and visceral organs of patients with RVCL has been unclear. Here, we report the clinicopathologic features of an autopsied patient with a heterozygous T249fs mutation in TREX1. The patient showed the clinical phenotype of vasculopathy with retinopathy, nephropathy, and stroke. CT with contrast enhancement demonstrated a tumorous lesion in the subcortical white matter. Histologically, the lesion consisted of confluent foci of necrosis with calcification and fibrous thickening of small vessel walls. TREX1 immunohistochemistry demonstrated positivity in the nuclei of cells in the CNS and visceral organs, indicating aberrant localization of the truncated protein, and the expression was remarkable in oligodendrocytes within the lesion, suggesting possible involvement of the protein in the pathomechanism of vasculopathy leading to white matter degeneration.