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.

• Authors: Jacopo C DiFrancesco, Francesca Novara, Orsetta Zuffardi, Antonella Forlino, Roberta Gioia, Federica Cossu, Martino Bolognesi, Simona Andreoni, Enrico Saracchi, Barbara Frigeni, Tiziana Stellato, Markus Tolnay, David T Winkler, Paolo Remida, Giuseppe Isimbaldi, Carlo Ferrarese
• Journal: Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology (Neurol Sci) Vol. 36 Issue 2 Pg. 323-30 (Feb 2015) ISSN: 1590-3478 [Electronic] Italy
• PMID: 25213617 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphoproteins
• Exodeoxyribonucleases
• three prime repair exonuclease 1

Topics

• Adult
• Cell Line
• Cell Nucleus (metabolism, pathology)
• Cytosol (metabolism, pathology)
• DNA Mutational Analysis
• Exodeoxyribonucleases (genetics, metabolism)
• Fibroblasts (metabolism, pathology)
• Follow-Up Studies
• Frameshift Mutation
• Hereditary Central Nervous System Demyelinating Diseases (drug therapy, genetics, metabolism, pathology)
• Humans
• Magnetic Resonance Imaging
• Male
• Microscopy, Confocal
• Phosphoproteins (genetics, metabolism)
• Retinal Diseases (drug therapy, genetics, metabolism, pathology)
• Tomography, X-Ray Computed
• Vascular Diseases (drug therapy, genetics, metabolism, pathology)