A WHRN mutation in nonhuman primates alters ocular biometric parameters but not retinal structure or function

Abstract

Purpose : Type II Usher syndrome is an autosomal recessive condition that causes vestibular dysfunction, hearing loss and visual impairment from progressive retinitis pigmentosa. We discovered a putative deleterious variant in exon 7 of WHRN predictive of disease in rhesus macaques, WHRN p.V495M. We then assessed ocular morphology and function in rhesus macaques homozygous for this WHRN mutation and wildtype (WT) controls.

Methods : Five rhesus macaques homozygous for the WHRN p.V495M mutation and five WT age-matched controls received a complete ophthalmic examination including intraocular pressure, A-scan ultrasounds, brainstem auditory evoked responses (BAER), spectral-domain optical coherence tomography (SD-OCT), and electroretinography. Temporal and nasal retinal thickness was manually measured 1.5 mm from the center of the fovea. Mann-Whitney tests were used to statistically compare the data; P<0.05 was considered statistically significant.

Results : Five WHRN mutant homozygotes (1 male and 4 females) and 5 WT control NHPs (2 males and 3 females) were included with a mean age of 9.4±1.8 (range: 6.8-11.3) years and 8.6±1.1 (range: 6.6-9.6) years, respectively. In the 5 WHRN homozygotes, BAER testing and scotopic and photopic full-field electroretinography indicated normal auditory and outer retinal function, respectively. Anterior chamber depth was significantly deeper in mutant homozygotes versus WT control NHPs; lens thickness was significantly thinner while vitreous and axial globe length were significantly longer in mutant homozygotes versus control NHPs (Figure 1). Nasal and temporal parafoveal total retinal thickness as well as those that of individual retinal layers did not statistically differ between the two groups (P>0.05, Table 1).

Conclusions : Interestingly, retinal structure and function as well as auditory function was normal in these nonhuman primates with a WHRN putative deleterious variant. However, ocular biometric values significantly differed from controls suggesting that this WHRN p.V495M variant may impact ocular development although additional phenotyping of cases and controls, particularly juveniles, is necessary to confirm these findings.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Figure 1. Ocular biometrics in a WHRN p.V495M mutation (HOM) and age-matched wildtype (WT) controls.

 

Table 1. Nasal and temporal retinal thickness in a WHRN p.V495M mutation (WHRN HOM) and age-matched wildtype (WT) controls.