Wolfram syndrome (WS) is an autosomal recessive disorder characterized by childhood onset of insulin dependent diabetes mellitus (DM), followed by optic atrophy (OA), blindness, and
deafness. Death from widespread neurodegeneration occurs in the third or fourth decades.
Mutations in the WFS1 gene, an endoplasmic reticulum (ER) membrane protein, cause WS
and in animal models of Wfs1 deficiency pancreatic islet β-cells exhibit high levels of ER
stress. β-cell death and neural degeneration may be related to high levels of ER stress in WS
patients but this is currently unknown. Aim 1 is to establish and maintain an Internet based
registry of patients with WS: http://wolframsyndrome.dom.wustl.edu/ Extensive clinical
information will be collated and analyzed to better define its natural history. Blood for genetic
analysis will be sent to a CLIA certified lab to evaluate genotype/phenotype correlations, and
to classify mutations that will be studied in Aims 2 and 3. This information will benefit patient
families and referring physicians by providing a genetic diagnosis and access to genetic
counseling. WS is so rare that no single institution can accumulate enough experience to
understand the natural history. The Registry will foster international collaborations to more
efficiently and systematically collect WS patients, their tissues, and clinical and experimental
data. Aim 2 is to define the relationship between WFS1 and ER stress in lymphocytes from
WS patients. Wfs1 has a protective function against ER stress in mouse β-cells, but it
remains to be determined how WFS1 mitigates ER stress in human cells. The results of
these studies may identify the aberrant disease mechanisms in WS patients. Aim 3 is to
evaluate therapeutic agents in lymphocytes from WS patients. ER stress and the associated
signaling events can be modulated by two chemical chaperones called PBA and TUDCA.
Immortalized lymphocytes from WS patients will be treated with PBA and TUDCA and the
cells will be examined for the alterations in biochemical and molecular indicators of E
Stress. Other chemicals will also be tested as they become available from the ongoing
chemical screens. These studies will set the grounds for potential proof-of-principal trials
and therapeutic opportunities to benefit individuals suffering from WS. Ultimately the results
of this study may provide the rational for employing similar agents to reduce ER stress in
patients with type two diabetes.