WHRN gene

• Overview
• Usher syndrome
• Retinitis pigmentosa
• Additional information
• References

Overview

Gene (OMIM no.)	WHRN (#607928)
Function of gene/protein	Scaffolding protein Localises to the ankle links in the stereocilia of the developing inner ear hair cells Required for correct post-natal development of stereocilia hair cells Localises to the periciliary membrane complex at the photoreceptor connecting cilium
Clinical phenotype (with OMIM phenotype no.)	Usher syndrome type 2D (#611383)1–2 Autosomal recessive hearing loss (#607084)3
Inheritance	Autosomal recessive
Ocular features	Retinitis pigmentosa
Visual function	Nyctalopia starting around adolescence or later Peripheral visual field loss Loss of central and colour vision in later life
Systemic features	Usher syndrome Congenital bilateral sensorineural hearing loss; mild to moderate in low frequencies, and severe to profound in high frequencies Failed newborn hearing screen or hearing difficulties suspected in infancy
Key investigations	Newborn hearing screen – otoacoustic emission and automated auditory brainstem response 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/cochlear implants Management of retinitis pigmentosa Management of Usher syndrome
Therapies under research	Gene therapy (pre-clinical)1,2
Further information	Genecards.org

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Additional Information

WHRN mutations are associated with Usher syndrome type 2D or non-syndromic deafness (DFNB31). The associated phenotypes are thought to be dependent on the mutation location within the two predominantly expressed variants (long and short). N-terminal mutations that affect the long isoform are found in Usher patients,^3,4 whereas mutations in the C-terminal region manifest as DFNB31.^5,6

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References

1. Zou J, Luo L, Shen Z, et al. Whirlin Replacement Restores the Formation of the USH2 Protein Complex in Whirlin Knockout Photoreceptors. Invest Ophthalmol Vis Sci. 2011;52(5):2343-2351.
2. Isgrig K, Shteamer JW, Belyantseva IA, et al. Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome. Mol Ther. 2017;25(3):780-791.
3. Ebermann I, Scholl HPN, Issa PC, et al. A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss. Hum Genet. 2007;121(2):203-211.
4. Audo I, Bujakowska K, Mohand-Said S, et al. A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family. Mol Vis. 2011;17(178):1598-1606.
5. Mburu P, Mustapha M, Varela A, et al. Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nat Genet. 2003;34(4):421-428.
6. Tlili A, Charfedine I, Lahmar I, et al. Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary non-syndromic recessive hearing loss. Hum Mutat. 2005;25(5):503-503.

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