Researchers at the Salk Institute and King Abdullah University of Science and Technology (KAUST) in Saudi Arabia have discovered a new underlying cause of Wiskott-Aldrich syndrome, a rare genetic disease that leads to bleeding and immune deficiencies in babies. Their findings, published in the journal Nature Communications on June 25, 2022, revolve around how cells cut and paste strands of RNA in a process called RNA splicing. The genetic mutations associated with Wiskott-Aldrich syndrome, they found, disrupt this process which, in turn, prevents numerous immune and anti-inflammatory proteins from being made correctly.
“This study not only suggests new targets for treating Wiskott-Aldrich syndrome with small molecule drugs, but also sheds new light on the basic biology of RNA splicing, an important and not fully understood process,” says co-corresponding author Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and holder of the Roger Guillemin Chair.
Babies with Wiskott-Aldrich syndrome begin to develop symptoms quickly after birth: itchy, scaly rashes, frequent bruises and nose bleeds are some of the first signs. Over time, they become prone to infections and are more likely than other children to develop autoimmune diseases and cancers. The only potential cure is a bone marrow transplant, which carries a host of complications and only works in some children.
Scientists have long known that Wiskott-Aldrich syndrome is caused by mutations in a gene on the X chromosome; the gene and the protein it encodes were named WASP after the syndrome. The WASP protein is found throughout cells in the blood and immune system, and one of its functions is to maintain these cells’ cytoskeletons, the microscopic networks of proteins that give cells their shape and organization. But changes to the cytoskeleton couldn’t explain all the symptoms.
Former Salk Postdoctoral Fellow Mo Li, now the head of KAUST’s Laboratory of Stem Cell and Regeneration, and Izpisua Belmonte wondered if WASP plays other roles — particularly in the nuclei of blood and immune cells, where genetic material is stored and processed.
To find out, they removed the WASP gene from stem cells and coaxed the cells to become macrophages or B cells, two types of immune cells impacted by the disease. They also collected cells from two patients with Wiskott-Aldrich syndrome and generated induced pluripotent stem cells (iPSCs) containing the disease-associated mutations in WASP. Then they compared the altered cells to normal macrophages and B cells.
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