Novel insight reported in the pathology of usher syndrome

Human Usher syndrome (USH) is the most common form of hereditary deaf-blindness and blindness affecting between 3 and 6 people in every 100,000. Individuals with USH can be deaf from birth, have vestibular dysfunction, and begin to suffer retinal degeneration from puberty, eventually losing their eyesight as the disease progresses. For sufferers with USH, cochlear implants can compensate for hearing loss in patients; however, there are currently no treatments for USH-associated blindness.

For over two decades, a research group led by Uwe Wolfrum, PhD, professor at the Institute of Molecular Physiology at Johannes Gutenberg University Mainz (JGU) has been investigating the mechanisms underlying USH. Wolfrum’s team partnered with Professor Reinhard Lührmann, PhD, at the Max Planck Institute for Biophysical Chemistry in Göttingen to identify a novel pathological mechanism leading to USH. The study was recently published in the journal Nucleic Acids Research titled, “SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes.”

In the current investigation, the researchers aimed to elucidate the molecular basis that leads to the degeneration of the light-sensitive photoreceptor cells in the eye in cases of USH. The team focused on one of the USH proteins, SANS. Synthesized from a gene called Usher syndrome type 1G (USH1G), SANS is expressed in the photoreceptors of the retina and supporting glia cells. Until now, how SANS contributes to pathogenic processes in the eye had remained ambiguous.

SANS was previously shown to function only in the cytosol and primary cilia. The team has discovered that to avoid dysfunctions that may develop disorders, the SANS protein plays an active role in correctly assembling sequences in the common cellular process called splicing. Splicing is necessary to connect different coding sequences of a gene in which the resulting mRNA is then used for protein biosynthesis. The splicing process is catalyzed in the nucleus by the spliceosome.

In the cell nucleus, SANS is vital for the release of tri-snRNPs from the Cajal bodies and their transfer to the nuclear speckles. In these nuclear speckles, tri-snRNP complexes bind to the spliceosome assembly to subsequently activate it. Additionally, SANS is also likely to be involved in recycling the tri-snRNP components back to the Cajal bodies. Thus, SANS plays a crucial role in correct pre-RNA splicing as a whole.

The investigators also noted that SANS acts as a scaffold protein that has multiple domains to which other proteins can dock, therefore making certain correct cellular function. Furthermore, the researchers have been able to demonstrate that absence of SANS and pathogenic mutations of the USH1G/SANS gene can lead to errors in the splicing of genes related to cell division and USH. Specifically, mutations in the USH1G/SANS gene ultimately leads to dysfunctions of the auditory and vestibular hair cells in the inner ear and of the photoreceptor cells of the retina, which are responsible for the development of sensory defects experienced by Usher syndrome patients. The authors concluded that they provided the first evidence that splicing dysregulation may participate in the pathophysiology of Usher syndrome.

The Hearing Journal connected with senior author, Uwe Wolfrum, to further discuss their study. Professor Wolfrum’s research interest is in photoreceptor and retina cell biology providing novel insights into the molecular intracellular transport. Additionally, his team investigates the molecular basis of USH and searches for gene-based therapeutics targeting neurodegeneration in the retina.

How is Usher syndrome diagnosed? What are the differences between the three subtypes?

Wolfrum: The human Usher syndrome [USH] is a complex, clinically and genetically heterogeneous disease that is the most common cause of deaf-blindness in humans. Three clinical subtypes of Usher syndrome are distinguished, USH type 1, USH type 2, and USH type 3, based on the severity and age of onset of retinal and inner ear impairments. USH type 1 is the most severe subtype, characterized by profound congenital deafness, vestibular dysfunction, and progressive vision loss beginning before puberty in the form of retinitis pigmentosa (RP). USH type 2 is characterized by moderate to severe congenital hearing loss, non-vestibular dysfunction, and later onset of RP; USH type 3 by variable RP and vestibular dysfunction combined with progressive hearing loss. These ophthalmologic and otolaryngologic diagnoses are accompanied by genetic diagnostics to identify the specific causative gene and pathogenic variant. Journals.LWW