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Amazing new insights into the pathology of Usher syndrome

The Usher syndrome 1G protein SANS regulates gene splicing, particularly of other Usher syndrome genes

Human Usher syndrome is the most common form of hereditary deaf-blindness. Affected individuals may be deaf from birth, may suffer from balance disorders and may lose their sight as the disease progresses. The research group of Prof. Dr. Uwe Wolfrum from the Institute of Molecular Physiology at Johannes Gutenberg University Mainz (JGU) has been working on research into Usher syndrome for around 25 years. His team, in cooperation with Prof. Dr. Reinhard Lührmann's research group at the Max Planck Institute for Biophysical Chemistry in Göttingen, has now discovered a new pathomechanism that leads to Usher syndrome. They found out that the Usher syndrome 1G protein SANS plays a decisive role in the regulation in the splicing process. Furthermore, they were able to show that defects in the SANS protein lead to errors in the splicing of genes associated with Usher syndrome and that this may trigger the disease.

Role of SANS in blindness still poorly understood.

"We are trying to clarify the molecular background that leads to the degeneration of the light-sensitive photoreceptor cells in the eye in Usher syndrome," explains Uwe Wolfrum about the research work. In Usher syndrome, hearing loss can be compensated with cochlear implants, but so far there are no therapies against blindness. For the current study, one of the Usher syndrome proteins, namely the USH1G protein called SANS, plays the central role. SANS is known from previous studies of the research group as a scaffolding protein. SANS has several domains to which other proteins can dock, which ensures correct cell function. Mutations in the USH1G/SANS gene lead to malfunctions of the auditory and vestibular hair cells in the inner ear and the photoreceptor cells of the retina, which are responsible for the sensory deficits of Usher syndrome patients.

Little is known about the role of SANS in the eye. Encoded by the USH1G gene, the protein is produced in retinal photoreceptors and glial cells. "Until now, we thought that SANS was involved in transport processes in the cell plasma as a scaffolding molecule," says Wolfrum. "But now, as part of his PhD work in the Mainz International PhD Programme, my colleague Adem Yildirim has discovered that SANS interacts with splicing factors and thereby regulates pre-RNA splicing."

SANS regulates splicing of pre-mRNA

Splicing, also known as splicing, is an important process on the way from the gene to the biosynthesis of the encoded protein. In this process, the non-coding introns or, in the case of alternative splicing, exons not required for the later protein variant are removed from the initially transcribed pre-mRNA. The resulting mRNA is then used for protein biosynthesis. The splicing process is catalysed in the cell nucleus by the spliceosome, a dynamic molecular machine of high complexity that is successively built up from numerous subcomplexes consisting of protein and RNA components.

"Now, surprisingly, we have found that SANS is also active in the cell nucleus and can modulate the splicing process there," Wolfrum describes the research results, which were published in the scientific journal Nucleic Acids Research. In the cell nucleus, SANS is responsible for the transfer of the tri-snRNP complex, a subcomplex of the spliceosome, from the Cajal bodies, the prefabrication factory of the complex, to the so-called "nuclear speckles". In this compartment, tri-snRNP complexes bind to the spliceosome apparatus to subsequently activate it. In addition, SANS is likely to be involved in the recycling of tri-snRNP components back to the Cajal bodies.

The absence of SANS and pathogenic mutations of the USH1G/SANS gene prevent the correct assembly of the spliceosome and its sequential activation. This prevents the correct splicing of other Usher syndrome-related genes and is likely to eventually lead to their dysfunction and thus to the disease. "We provide the first evidence that dysregulation of splicing is involved in the pathophysiology of Usher syndrome," the authors summarise their research findings. Wolfrum continues: "In addition to the new insights into the splicing mechanism, we have also identified new targets that we would like to use for future treatment and therapy of Usher syndrome."


Prof. Dr. Uwe Wolfrum
Molekulare Zellbiologie
Institut für Molekulare Physiologie (IMP)
Johannes Gutenberg-Universität Mainz
55099 Mainz

Original publication

Adem Yildirim, Sina Mozaffari-Jovin et al.
SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes
Nucleic Acids Research, 22. Mai 2021
DOI: 10.1093/nar/gkab386