TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy

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• 作者：Jacopo C. DiFrancesco ; Francesca Novara ; Orsetta Zuffardi…
• 关键词：Retinal vasculopathy with cerebral leukodystrophy ; TREX1 ; Hereditary systemic angiopathy ; Systemic microangiopathy ; Cerebral calcifications ; Brain pseudotumoral lesion
• 刊名：Neurological Sciences
• 出版年：2015
• 出版时间：February 2015
• 年：2015
• 卷：36
• 期：2
• 页码：323-330
• 全文大小：1,274 KB
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• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Neurology
  Neuroradiology
  Neurosurgery
  Psychiatry
  
• 出版者：Springer Milan
• ISSN：1590-3478

文摘

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3′--DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here we describe the second case of RVCL with systemic involvement, characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, osteonecrosis, renal and hepatic failure. The genetic screening of TREX1 in this patient revealed the novel heterozygous T270fs mutation on the C-terminal region. On the same gene, we found the V235fs mutation, formerly shown in RVCL, in one patient previously reported with HSA. These mutations lead to important alterations of the C-terminal of the protein, with the loss of the transmembrane helix (T270fs) and the insertion of a premature stop codon, resulting in a truncated protein (V235fs). Functional analysis of T270fs-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region. RVCL with systemic involvement is an extremely rare condition, whose diagnosis is complex due to multiorgan manifestations, unusual radiological and histopathological findings, not easily attributable to a single disease. It should be suspected in young adults with systemic microangiopathy involving retina, liver, kidney, bones and brain. Here we confirm the causative role played by TREX1 autosomal dominant fs mutations disrupting the C-terminal of the protein, providing a model for the study of stroke in young adults.