C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.

Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Nature Genetics (Impact Factor: 29.65). 10/2007; 39(9):1068-70. DOI: 10.1038/ng2082
Source: PubMed

ABSTRACT Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Migraine has an important genetic component. The prototypic monogenic form of migraine is hemiplegic migraine, a rare subtype of migraine with aura, for which three causative genes have been identified. Studies of transgenic animal models have substantially improved our understanding of the molecular pathophysiology of this monogenic model disease as well as of migraine in general. Beyond this, there are other (rarer) monogenic forms of migraine, e.g., in the context of hereditary mostly vascular syndromes such as CADASIL. By contrast, the common types of migraine with and without aura are genetically complex. With the identification of the first robust genetic risk variants in large genome-wide association studies, our knowledge in this still dynamically expanding field has substantially increased. This review summarizes the current status of migraine genetics, with a special focus on hemiplegic migraine as well as the most recent findings in complex migraine genetics. In addition, the first preliminary findings on the genetics of other types of primary headache disorders (cluster headache, tension-type headache) are briefly reviewed.
    Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 07/2014; · 1.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cerebroretinal vasculopathy (CRV) and the related diseases hereditary endotheliopathy with retinopathy, neuropathy, and stroke (HERNS), hereditary vascular retinopathy (HVR) and hereditary systemic angiopathy (HSA) [subsequently combined as retinovasculopathy and cerebral leukodystrophy (RVCL)] are devastating autosomal-dominant disorders of early to middle-age onset presenting with a core constellation of neurologic and ophthalmologic findings. This family of diseases is linked by specific mutations targeting a core region of a gene. Frameshift mutations in the carboxyl-terminus of three prime exonuclease-1 (TREX1), the major mammalian 3′ to 5′ DNA exonuclease on chromosome 3p21.1-p21.3, result in a systemic vasculopathy that follows an approximately 5-year course leading to death secondary to progressive neurologic decline, with sometimes a more protracted course in HERNS. Neuropathological features include a fibrinoid vascular necrosis or thickened hyalinized vessels associated with white matter ischemia, necrosis and often striking dystrophic calcifications. Ultrastructural studies of the vessel walls often demonstrate unusual multilaminated basement membranes.
    Brain Pathology 09/2014; 24(5). · 4.35 Impact Factor
  • Source
    02/2015; 2(1):e55.


Available from
May 28, 2014