title: 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.affiliation: Department of Neurology, San Gerardo Hospital, Via Pergolesi 33, 20900, Monza, Italy, jacopo.difrancesco@unimib.it.
authors.forename: Jacopo C
authors.initials: JC
authors.lastname: DiFrancesco
authors.forename: Francesca
authors.initials: F
authors.lastname: Novara
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.forename: Roberta
authors.initials: R
authors.lastname: Gioia
authors.forename: Federica
authors.initials: F
authors.lastname: Cossu
authors.forename: Martino
authors.initials: M
authors.lastname: Bolognesi
authors.forename: Simona
authors.initials: S
authors.lastname: Andreoni
authors.forename: Enrico
authors.initials: E
authors.lastname: Saracchi
authors.forename: Barbara
authors.initials: B
authors.lastname: Frigeni
authors.forename: Tiziana
authors.initials: T
authors.lastname: Stellato
authors.forename: Markus
authors.initials: M
authors.lastname: Tolnay
authors.forename: David T
authors.initials: DT
authors.lastname: Winkler
authors.forename: Paolo
authors.initials: P
authors.lastname: Remida
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Isimbaldi
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrarese
mesh_terms: D000328:Adult; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003600:Cytosol / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005500:Follow-Up Studies; D016368:Frameshift Mutation; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D012164:Retinal Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014057:Tomography, X-Ray Computed; D014652:Vascular Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D010750:Phosphoproteins; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1