Characteristic Ocular Features in Cases of Autosomal Recessive PROM1 Cone-Rod Dystrophy

Abstract

Purpose To define characteristic ocular features in a group of patients with autosomal recessive (AR) PROM1 cone-rod dystrophy (CRD). Methods Three males and one female from three unrelated families were first seen at the ages of 15 to 22 years and diagnosed with CRD. Clinical testing available for review included full-field electroretinogram (ERG) in three patients, as well as near-infrared autofluorescence (NIR-AF), spectral-domain optical coherence tomography (SD-OCT), and color fundus photography in all four patients. Whole exome sequencing (WES) was performed on all cases, and whole genome sequencing (WGS) was performed in two families. Results WES found compound heterozygous PROM1 variants in one isolated male, plus heterozygous variants in the remaining patients. WGS uncovered deleterious PROM1 variants in these two families. ERG showed markedly reduced cone-isolated amplitudes and variably reduced rod-isolated amplitudes. The dark-adapted combined rod and cone responses demonstrated notably reduced a-wave amplitudes and moderately reduced b-waves, and the resultant waveform resembled the normal rod-isolated response. On fundus examination, oval-shaped macular lesions were observed, as were several small, circular hypoautofluorescent lesions within the posterior pole on NIR-AF. Three patients showed extramacular circular atrophic lesions. Conclusions The autofluorescence changes, peripheral retinal abnormalities, and ERG findings have not been emphasized in previous reports of AR PROM1 , but they became a recognizable phenotype in this cohort of patients. A similar constellation of findings may be observed in CRD due to CDHR1, a functionally related gene. The pattern of abnormalities reported herein may help to focus genetic screening in patients with these findings.

The Interplay between Peripherin 2 Complex Formation and Degenerative Retinal Diseases

“…Prominin-1 is a membrane protein with five transmembrane domains that localizes at the open end of newly synthesized discs in ROS, thus opposite to the localization of Prph2 [51][52][53][54][55]. The vital role of Prominin-1 in the structural integrity of the photoreceptor OS is supported by the finding that mutations in Prominin-1 are connected to retinal diseases causing degeneration of the photoreceptors [54,[56][57][58][59]. Earlier studies on Prominin-1 demonstrated that it shows a binding preference for curved membranes, but does not induce the curvature itself [60,61].…”

Exocyst-mediated membrane trafficking of the lissencephaly-associated ECM receptor dystroglycan is required for proper brain compartmentalization

“…This group includes several proteins that play a role in eye morphogenesis in Drosophila and humans ( Jukam and Desplan, 2011 ; Mahato et al, 2018 ; Marrone et al, 2011a ; Ray et al, 2020 ). Moreover, these factors are not only associated with various ocular dystrophies but also involved in cancer development and regulation of stem cell maintenance and differentiation, cell growth, and metabolism ( Cehajic-Kapetanovic et al, 2019 ; Collison et al, 2019 ; Jamal et al, 2020 ; Lu et al, 2019 ; Priedigkeit et al, 2021 ; Wu et al, 2020 ). For example, in Drosophila, prominin (Prom), a homolog of human CD133, maintains mitochondrial function, regulates body size and weight, and influences animal longevity by controlling insulin and TOR signaling ( Ryu et al, 2019 ; Wang et al, 2019 ; Zheng et al, 2019 ).…”

Childhood-onset genetic cone-rod photoreceptor diseases and underlying pathobiology

“…It is expressed in photoreceptors predominantly at the base of the outer segments in the protrusions of disk membranes ( Fig. 3 a) [35] , [36] , [37] . Prominin-1 interacts with cadherin related family member 1 (CDHR1) and actin to promote normal photoreceptor disk morphology [38] .…”