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.
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Acknowledgments
This paper is dedicated to the memory of our colleague Dr. Mario Savoiardo, Neurological Institute “Carlo Besta” of Milano, who contributed to the management of patient 1 and deceased during the writing of the manuscript. We thank Prof. Giovanni Zatti (Orthopedic Department, S. Gerardo Hospital, Monza, Italy), and Dr. Franca Di Nuovo (G. Salvini Hospital, Garbagnate, Italy) for their contribution. We thank Angelo Gallanti, Department of Molecular Medicine, University of Pavia, Italy, for fibroblasts culture support. This study was supported by grant no. GGP10121C to O. Zuffardi from Telethon Fondazione Onlus, Italy.
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DiFrancesco, J.C., Novara, F., Zuffardi, O. et al. TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy. Neurol Sci 36, 323–330 (2015). https://doi.org/10.1007/s10072-014-1944-9
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DOI: https://doi.org/10.1007/s10072-014-1944-9