Gene Splicing Dysfunction in Usher Syndrome

Article: Remarkable new insights into the pathology of Usher syndrome
Source: Johannes Gutenberg Universität Mainz (Germany), via ScienceDaily
Published: July 12, 2021
Article: Splicing Dysfunction Identified in Usher Syndrome
Source: Genetic Engineering & Biotechnology News
Published: July 14, 2021

When SANS (siSANS) is lacking or dysfunctional,
tri-snRNA complexes are not released from the Cajal
bodies (red) but rather accumulate there (green).

Usher syndrome (USH) is the most common cause of combined hereditary deafness and blindness. Alternatively known as retinitis pigmentosa–dysacusis syndrome, vision loss results from progressive degeneration of the photoreceptors in the retina (RP in this case) within the first or second decade of life. More than a dozen genes and loci have been identified as contributing to the disease; however, its pathophysiology is not completely understood. Researchers in Germany investigating the pathological mechanism underlying Usher syndrome discovered that defects in a protein called SANS, synthesized from a gene named Usher syndrome type 1G (USH1G), leads to errors in pre-mRNA splicing related to cell division, ultimately leading to ciliopathy of the photoreceptors (and hair cells in the inner ear, accounting for the deafness aspect of the syndrome). Specifically, the authors explained, "We show that SANS is found in Cajal bodies and nuclear speckles, where it interacts with components of spliceosomal sub-complexes such as SF3B1 and the large splicing cofactor SON but also with PRPFs and snRNAs related to the tri-snRNP complex. SANS is required for the transfer of tri-snRNPs between Cajal bodies and nuclear speckles for spliceosome assembly and may also participate in snRNP recycling back to Cajal bodies." This new finding contrasts with earlier thinking that SANS was simply a scaffold molecule that participates in transport processes in the cytosol and cilia at the cell surface. Lack or dysfunction of SANS prevents the spliceosome in the nucleus from being correctly assembled and activated, without which genes are not correctly spliced, ultimately leading to the clinical manifestation of Usher syndrome.

My rating of this study: ⭐⭐

Yildirim A, Mozaffari-Jovin S, Wallisch A, et al. "SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes." Nucleic Acids Research.  49(10):5845–5866. 4 June 2021. https://doi.org/10.1093/nar/gkab386