CLRN1 gene

• Overview
• Usher syndrome
• Retinitis pigmentosa
• References

Overview

Gene (OMIM no.)	CLRN1 (#606397)
Function of gene/protein	Transmembrane protein Required for the normal development and maintenance of the inner ear stereocilia hair cells Localises to the retinal Müller glial cells May be involved in synapse development and function
Clinical phenotype (with OMIM phenotype no.)	Usher syndrome type 3A (#276902)1–2 Autosomal recessive retinitis pigmentosa (#607084)3
Inheritance	Autosomal recessive
Ocular features	Retinitis pigmentosa
Visual function	Nyctalopia typically starting after adolescence Peripheral visual field loss Loss of central and colour vision in later life
Systemic features	Usher syndrome Progressive bilateral sensorineural hearing loss with variable onset (post-lingual) and severity Vestibular abnormalities present in some patients
Key investigations	Pure tone audiometry Electrophysiology Fundus autofluorescence (FAF): a ring of hyper-AF in the macula Optical coherence tomography (OCT): progressive loss of outer retinal structures which spares the fovea initially; cystoid macular oedema may be detected Kinetic perimetry
Molecular diagnosis	Next generation sequencing Targeted gene panels (retinal and deafness) Whole exome sequencing Whole genome sequencing Targeted exome sequencing
Management	Hearing aids Management of retinitis pigmentosa Management of Usher syndrome
Therapies under research	Gene therapy (pre-clinical)4–7 Small molecules (pre-clinical)8
Further information	Medline Plus

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References

1. Joensuu T, Hamalainen R, Yuan B, et al. Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3. Am J Hum Genet. 2001;69(4):673-684.
2. Adato A, Vreugde S, Joensuu T, et al. USH3A transcripts encode clarin-1, a four- transmembrane-domain protein with a possible role in sensory synapses. Eur J Hum Genet. 2002;10(6):339-350.
3. Khan MI, Kersten FFJ, Azam M, et al. CLRN1 Mutations Cause Nonsyndromic Retinitis Pigmentosa. Ophthalmology. 2011;118(7):1444-1448.
4. Dinculescu A, Stupay RM, Deng WT, et al. AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy. PLoS One. 2016;11(2):e0148874.
5. Geng R, Omar A, Gopal SR, et al. Modeling and Preventing Progressive Hearing Loss in Usher Syndrome III. Sci Rep. 2017;7(1):13480.
6. Dulon D, Papal S, Patni P, et al. Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome. The Journal of clinical investigation. 2018;128(8):3382-3401.
7. György B, Meijer EJ, Ivanchenko MV, et al. Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate. Molecular therapy Methods & clinical development. 2019;13:1-13.
8. Alagramam KN, Gopal SR, Geng R, et al. A small molecule mitigates hearing loss in a mouse model of Usher syndrome III. Nat Chem Biol. 2016;12(6):444-451.

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