Salk researchers discover how RNA splicing goes awry in rare immune disease

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"... “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 ...
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 ... But changes to the cytoskeleton couldn’t explain all the symptoms. ...
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. ...
Immune cells lacking WASP, or containing mutations in the WASP gene, appeared different right away; there were many more clusters—known as nuclear speckles—in the centers of diseased cells. For a protein to be produced by a cell, the DNA encoding it is first transcribed into a strand of RNA. Often, this initial strand contains more genetic material than is needed; this is where RNA splicing comes in. Proteins in nuclear speckles cut and paste bits of the initial RNA strand into its final instructions for a protein. ...
Additional experiments revealed that repairing WASP mutations fixes these RNA splicing defects. What’s more, lowering levels of an RNA-splicing factor, SRSF2, can prevent the problems. These results suggest that drugs targeting SRSF2 could treat Wiskott-Aldrich syndrome in humans, the researchers say. ..."

From the abstract:

"The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Together our data reveal that WASP is a nexus regulator of RNA splicing that controls the transcription of splicing factors epigenetically and the dynamics of the splicing machinery through liquid-liquid phase separation."

Salk researchers discover how RNA processing goes awry in rare immune disease - Salk Institute for Biological Studies Findings could lead to new treatments for Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing (open access)

Fig. 1: Generation of isogenic iPSC models of WAS.