Recapitulating X-Linked Juvenile Retinoschisis in Mouse Model by Knock-In Patient-Specific Novel Mutation

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• X-linked juvenile retinoschisis (XLRS) is a genetic retinal disorder caused by mutations in the RS1 gene.
• XLRS leads to significant visual impairment and blindness, necessitating effective therapeutic strategies.
• Developing patient-specific animal models is crucial for advancing gene therapy research.

Purpose of the Study:

• To generate a knock-in mouse model harboring the specific p.Y65X mutation identified in a patient family with XLRS.
• To characterize the retinal phenotype and electroretinographic (ERG) abnormalities in the generated RS1-KI mice.
• To establish a valuable preclinical tool for developing genome editing-based gene therapies for XLRS.

Main Methods:

• Recruitment of an XLRS patient family and identification of the causative RS1 mutation (p.Y65X).
• Generation of a knock-in mouse model (RS1-KI) using TALEN technology to introduce the patient-specific mutation.
• Assessment of retinal structure and function using electroretinography (ERG) and histological analysis.

Main Results:

• The RS1-KI mice exhibited significantly decreased b-wave amplitudes in ERG recordings, indicating impaired retinal function.
• Histological examination revealed retinal structural abnormalities in RS1-KI mice, including disorganization of nuclear layers and photoreceptor degeneration.
• The generated knock-in model accurately recapitulates key pathological features of human XLRS.

Conclusions:

• The novel RS1-KI mouse model carrying the patient-specific p.Y65X mutation is successfully generated.
• This model demonstrates functional and structural retinal deficits consistent with XLRS.
• The RS1-KI mice serve as a valuable preclinical platform for evaluating genome editing strategies for XLRS treatment.