Established in 2016, the RVCL Research Center at Washington University is leading an effort to coordinate global research on retinal vasculopathy with cerebral leukoencephalopathy (RVCL), provide comprehensive and multidisciplinary patient care and initiate clinical studies and drug trials.

Our aims are to serve as a resource to help families, educate physicians about the disease and increase overall awareness of RVCL.

Together with collaborators from around the world, studies are underway to better understand and treat this very rare disease.

This section presents some of the latest scientific findings and publications related to RVCL.


Approximately 42 unrelated families worldwide have been identified with RVCL. Our families are located not only  in the USA but also in Australia, Germany, France, the Netherlands, Spain, Mexico, Japan, China, Turkey, Switzerland and Italy.

This autosomal dominant disorder features three types of mutations all of which are located at or beyond valine-235 of the 314 amino acid protein. The most dominant mutations are frame-shift mutations of TREX1 that produce a truncated protein. A second type of mutation is a Stop mutation in which the translation of TREX1 abruptly ends. Another type of mutation simply deletes amino acids in this region but it retains the amino acids after the deletion. While all of these mutation have not yet been modeled, we believe the common effect is the production of a protein that is mislocalized throughout cells instead of being anchored on the endoplasmic reticulum. We have called this aberrant localization process “TREX on the loose.”

DNA sequencing analysis for TREX1 in patients with RVCL. We recommend comparing sequencing results with GENBANK reference sequence: NM_033629.  In this example of DNA sequencing analysis, the four different bases of DNA are each shown as a different color. The base sequence is ‘in-frame’ or normal up to the point where an additional base has been inserted (G-insertion). The sequence now becomes scrambled (out of frame) eventually causing a premature ‘stop’ when the gene is translated into a shortened dysfunctional protein. This demonstrates also that one copy of TREX1 ‘works’ while the other is dysfunctional. This example is the V235Gfs*6 mutation.


The wild-type protein translated from the TREX1 gene consists of 314 amino acids (~ 32 kDa) and is encoded by a single exon on chromosome 3p21TREX1 consists of three domains important for its role as a DNA repair enzyme (i.e., exonuclease domains I, II, and III). TREX1 also has an extended C-terminal “tail” domain of ~ 70 amino acids containing a leucine-rich sequence required for its endoplasmic reticulum (ER) localization.

A schematic diagram of normal TREX1 protein. TREX1 has three exonuclease domains and a tail region. In RVCL, the tail is shortened or deleted.

As described above, RVCL results from a mutation in the tail domain that changes the protein reading frame, introduces a stop codon, and thus causes a premature termination leading to partial loss of the tail. As a result, TREX1 loses it ability to remain in the ER and becomes mislocalized throughout the cell. Of the 37 identified families worldwide with RVCL, 16 unrelated kindreds have a particular mutation identified on the protein level described as V235G fs*6. This means that in TREX1, the amino acid valine changes to a glycine at amino acid #235. Although normal TREX1 protein is 314 amino acids long, this mutation causes the protein to interrupt its normal sequence, add 6 ‘foreign’ amino acids and then terminate abruptly knocking out the normal tail sequence.

“TREX on the loose.” This picture was taken by a confocal microscope demonstrating how abnormal TREX1 protein malfunctions. In the picture to the left, the normal pattern of TREX1 (green) is outside of the nucleus (red). In the case of abnormal TREX1 (right panel), it become distributed throughout the cell (yellow and green). Scientifically: human HEK293 cells show transiently expressed fluorescent protein (FP)-tagged TREX1 proteins in green and TOPRO3 staining of nuclei. The overlay is in yellow.

For reasons that are as yet unclear, most people who carry these heterozygous TREX1 tail mutations live a fairly normal life until middle age, when vision and brain damage begin. Progressive deterioration proceeds over a 5 to 15 year period. New studies conducted by our laboratory have identified that TREX1 is expressed by a subset of human brain microglia cells that also are often close to blood vessels. However,   TREX1 clusters densely in microglia cells in proximity to brain lesions of RVCL patients. Further studies are needed to determine how clustered TREX1 may impact the symptoms of RVCL.

In addition to RVCL, mutations in other areas of TREX1 play major roles in a variety of neurovascular and autoimmune-related disorders such as Aicardi-Goutieres syndrome, chilblain lupus, and Cree encephalitis. TREX1 mutations also have been linked to systemic lupus erythematosus (SLE) and Sjögren’s syndrome.


There are two known functions for TREX1:

DNA Sensor

TREX1 was originally discovered and identified as the “3 prime repair exonuclease 1” that cleans up and digests DNA debris that is generated when tissue is damaged or cells die. It degrades single-stranded DNA ~4-fold more efficiently than double-stranded DNA. TREX1 is also important for handling DNA from viruses that invade and infect cells.

Sugar Sensor

A newly discovered function of TREX1 is in overseeing the ‘sugar polishing’ step (i.e., glycosylation) for newly made proteins. Thus, TREX1 interacts with cellular machinery (the oligosaccharyltransferase or “OST” complex) to add N-glycans to proteins as they are produced. These glycans are important for modulating the function and stability of proteins.

When the sugar polishing function is disrupted, TREX1 no longer can bind to its partner proteins in the OST complex. This leads to the buildup of glycans. The disruption of this important interaction also may diminish blood vessel life-span and integrity and lead to disturbances in the immune system. These studies also identified an anthracycline antibiotic (Aclarubicin) that corrected the defect in both mouse disease models and in human patient cells. Studies are underway to better understand and expand on these exciting discoveries. Additionally, human clinical trials are in development.

Disease Models

Our research utilizes two types of models: human lymphoblast cell lines and mouse disease models. For the former, we prepare immortalized EBV-transformed patient B cells. Secondly, we and others have developed TREX1 mouse models that knock out of mouse TREX1 (TREX1-/-) or knock in human RVCL TREX1 mutation (V235fs-KI).

Parul Kothari, MD, PhD, who studied this disease at Washington University, wrote her doctoral dissertation on these studies.

TREX1 Reagents

Our teams have produced recombinant human TREX1 and recombinant RVCL TREX1 as well as antibodies to normal TREX1. These reagents are valuable tools to study the disease in vitro (in the test tube) as well as in vivo (in living systems).

Researchers at the RVCL Research Center continue to seek a better understanding of the disease process and to find an effective treatment to replace, bypass, correct or negate the effects of defective TREX1 protein.

For additional information on RVCL, see our review for the National Organization for Rare Disorders (NORD).

RVCL review on NORD website