SEARCHING FOR NEW GENES THAT CAUSE USHER SYNDROME.

Area of Science:

• Genetics
• Ophthalmology
• Audiology

Background:

• Usher syndrome (USH) is a leading genetic cause of combined vision and hearing impairment.
• Identifying novel genes associated with USH is crucial for understanding disease mechanisms and developing therapies.

Purpose of the Study:

• To identify novel Usher syndrome (USH) candidate genes using a large-scale knockout (KO) mouse phenotyping dataset.
• To screen 9,139 KO mouse lines for concurrent retinopathy and hearing abnormalities.

Main Methods:

• Evaluated phenotype data from single-gene KO mice generated by the International Mouse Phenotyping Consortium (IMPC).
• Assessed concurrent retinopathy and hearing abnormalities via ear and eye examinations and histopathology.
• Utilized bioinformatic tools to predict protein interactions, molecular functions, signaling pathways, and expression of human orthologs.

Main Results:

• Identified 18 KO mouse lines with both hearing abnormality and retinopathy.
• Found partial overlap in molecular functions and signaling pathways between candidate gene orthologs and known USH genes.
• Highlighted specific genes (e.g., FER, DYRK1B, ADIPOR1, ATP8B1, MPDZ, CHSY1, IDUA, CSTB, SPRED1) with predicted roles in ciliopathies, retinal degeneration, or hearing impairment, and proximity to USH loci.

Conclusions:

• A large-scale screen of KO mouse lines successfully identified 18 candidate genes associated with USH phenotypes.
• These candidate genes, exhibiting retinal and inner ear abnormalities in mice, warrant further investigation for causative roles in human Usher syndrome.
• The findings provide a foundation for future research into the genetic basis of Usher syndrome and related ciliopathies.