The Efemp1^R345W Macular Dystrophy Mutation Causes Amplified Circadian and Photophobic Responses to Light in Mice

Abstract

PurposeThe R345W mutation in EFEMP1 causes malattia leventinese, an autosomal dominant eye disease with pathogenesis similar to an early-onset age-related macular degeneration. In mice, Efemp1R345W does not cause detectable degeneration but small subretinal deposits do accumulate. The purpose of this study was to determine whether there were abnormal responses to light at this presymptomatic stage in Efemp1R345W mice.MethodsResponses to light were assessed by visual water task, circadian phase shifting, and negative masking behavior. The mechanism of abnormal responses was investigated by anterior eye exam, electroretinogram, melanopsin cell quantification, and multielectrode recording of retinal ganglion cell activity.ResultsVisual acuity was not different in Efemp1R345W mice. However, amplitudes of circadian phase shifting (P = 0.016) and negative masking (P < 0.0001) were increased in Efemp1R345W mice. This phenotype was not explained by anterior eye defects or amplified outer retina responses. Instead, we identified increased melanopsin-generated responses to light in the ganglion cell layer of the retina (P < 0.01).ConclusionsEfemp1R345W increases the sensitivity to light of behavioral responses driven by detection of irradiance. An amplified response to light in melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) is consistent with this phenotype. The major concern with this effect of the malattia leventinese mutation is the potential for abnormal regulation of physiology by light to negatively affect health.

A single-cell transcriptome atlas of the aging human and macaque retina

“…7 e and f). Mutations of EFEMP1 can lead to macular dystrophy [ 37 ], and the expression of EFEMP1 was high in human and macaque foveal MGs (Fig. 7 e and f).…”

ROP18-Mediated Transcriptional Reprogramming of HEK293T Cell Reveals New Roles of ROP18 in the Interplay Between Toxoplasma gondii and the Host Cell

“…As shown in Supplementary Table S4, ROP18 altered the expressions of 15 eye disease-related genes, including EFEMP1, SLC7A14, MIP (major intrinsic protein of lens fibe), COL25A1, CFB, SLC38A8, CFI, RIMS1, CABP4, RP1L1, CRYAB, PROM1, CRX, KCNJ13, and VCAN. Previous studies showed that EFEMP1 (Lin et al, 2018;Thompson et al, 2019), SLC7A14 (Jin et al, 2014), and RP1L1 (Albarry et al, 2019) are linked to macular degeneration or retinitis pigmentosa; COL25A1, which encodes a membrane associated collagen, is associated with oculomotor neuron development (Shinwari et al, 2015). Also, RP1L1 (Fujinami-Yokokawa et al, 2019), PROM1 Supplementary Table S2.…”

A single-cell transcriptome atlas of the aging human and macaque retina

“…7ef). Mutations of EFEMP1 can lead to macular dystrophy [50], and the expression of EFEMP1 was high in human and macaque foveal MGs (Fig. 7e-f).…”