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

Abstract

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3'-5' 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.

Tumefactive lesions in retinal vasculopathy with cerebral leucoencephalopathy and systemic manifestations (RVCL-S): a role for neuroinflammation?

“…Another patient with RVCL-S also developed punctate skin lesions on the thighs9 and yet another was reported to have skin lesions 10. In the first of these cases, as in our case, pathology was consistent with ‘vasculitis’.…”

Monogenic causes of stroke: now and the future

“…RVCL is caused by frameshift mutations in the carboxyl-terminus of the gene, resulting in the expression of DNAse III with a truncated C-terminus which has functions in the localisation of DNAse III in the endoplasmic reticulum. Functional analyses have shown that these mutations cause cellular mislocalization [24], rather than a loss of enzymatic activity.…”

“…These patients develop systemic small vessel vasculopathy resulting in the premature infarction and necrosis of tissue, manifesting as Raynaud's phenomenon, hepatic micronodular cirrhosis, renal dysfunction and osteonecrosis [24].…”

“…The TREX1 gene encodes the most abundant DNA exonuclease in the mammalian cell, DNAse III or Three prime Repair Exonuclease [22]. DNAse III is thought to have roles in DNA repair, as it is normally localised in the endoplasmic reticulum, but is translocated to the nucleus following oxidative DNA insult [24]. RVCL is caused by frameshift mutations in the carboxyl-terminus of the gene, resulting in the expression of DNAse III with a truncated C-terminus which has functions in the localisation of DNAse III in the endoplasmic reticulum.…”

Genetics of vascular dementia – review from the ICVD working group

“…The typical features of retinal vasculopathy with cerebral leukodystrophy are retinal vasculopathy, cognitive impairment, migraine, psychiatric abnormalities, and seizures, as well as hepatic and renal dysfunction [11, 12]. The disease is due to the TREX1 gene and associated both with CSVD neuroimaging features and, in some cases, pseudotumoral lesions surrounded by vasogenic edema [13–15]. …”