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Multicenter Study
. 2019 Jun 5;2(6):e195752.
doi: 10.1001/jamanetworkopen.2019.5752.

Clinical and Molecular Characterization of PROM1-Related Retinal Degeneration

Jasmina Cehajic-Kapetanovic  1   2 , Johannes Birtel  3 , Michelle E McClements  1 , Morag E Shanks  4 , Penny Clouston  4 , Susan M Downes  1   2 , Peter Charbel Issa  1   2   3 , Robert E MacLaren  1   2
Affiliations
Multicenter Study

Clinical and Molecular Characterization of PROM1-Related Retinal Degeneration

Jasmina Cehajic-Kapetanovic et al. JAMA Netw Open. .

Abstract

Importance: The PROM1 gene, commonly associated with cone-rod dystrophies, may have dominant or recessive phenotypes that influence disease onset and severity.

Objective: To characterize the clinical phenotype and molecular genetic variations in patients with PROM1 variants.

Design, setting, and participants: This case-series study was conducted at 2 specialist retinal genetics clinics and examined 19 consecutively enrolled patients with PROM1-related retinal degeneration. Data were collected and analyzed from May 2018 to December 2018.

Main outcomes and measures: Results of ophthalmic examination, retinal imaging, and molecular genetic analysis by next-generation sequencing.

Results: Of 19 patients, 13 (68%) were women, and age ranged from 11 to 70 years. All patients presented with central visual loss, with or without photophobia. Individuals with recessive variants commonly had severe loss of visual acuity by their 20s, whereas the dominant variant was associated with a milder phenotype, with most patients retaining good vision into late adulthood. The recessive cases were associated with a panretinal dystrophy of cone-rod phenotype with early macular involvement, whereas the dominant variants were associated with a cone-rod phenotype that was restricted to the macula with predominantly cone dysfunction. Next-generation sequencing identified 3 novel and 9 previously reported variants in PROM1. Recessive mutations included 6 truncating variants (3 nonsense and 3 frameshift), 4 splice site variants, and 1 missense variant. All 6 dominant variants were associated with a c.1117C>T missense variant. The variants were distributed throughout the PROM1 genomic sequence with no specific clustering on protein domains.

Conclusions and relevance: In this case-series study, PROM1 recessive variants were associated with early-onset, severe panretinal degeneration. The similar phenotypes observed in patients with homozygous missense variants and splice site variants compared with similarly aged patients with truncating variants suggests that all recessive variants have a null (or loss of function close to null) outcome on PROM1 function. In contrast, the dominant missense cases were associated with a milder, cone-driven phenotype, suggesting that the dominant disease is preferentially associated with cones. This has implications for the development of treatments for this severely blinding disease, and adeno-associated viral vector-based gene therapy and optogenetics could become successful treatment options.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McClements reported receiving personal fees from and consulting for Nightstar Therapeutics outside the submitted work. Dr Downes reported receiving grants from Retina UK and Fight for Sight outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Representative Images of PROM1-Related Retinal Degeneration Associated With Recessive and Dominant Genotypes
From left to right, images are color photographs, fundus autofluorescence photographs, and optical coherence tomography images. A, Images of patient AR6; visual acuity, 1.3 OD and 1.3 OS; c.199C>T variant. B, Images of patient AR5; visual acuity, 1.6 OD and 1.4 OS; c.1354dup variant. C, Images of patient AR9; visual acuity, 1.7 OD and 1.6 OS; c.1142-1G>A variant. D, Images of patient AR10; visual acuity, light perception in both eyes; c.1853T>G variant. E, Images of patient AD5; visual acuity, 0.1 OD and 0.0 OR; c.1117C>T variant.
Figure 2.
Figure 2.. Association of Visual Acuity With Age at Time of Presentation in All PROM1 Variants Reported to Date
The mean logMAR score between the right and left eyes is plotted against age. CF indicates counting fingers; HM, hand movements; NPL, no perception of light; and PL, perception of light.
Figure 3.
Figure 3.. Schematic Representation of PROM1 and Associated Variants
The PROM1 protein is shown as a white bar with the respective protein domains depicted in different colors. Recessive variants are shown above, and dominant variants are shown below. Variants from the current study appear in bold, and novel variants appear in red. For splice site and frameshift variants, the arrow indicates the location of the first affected amino acid. Variants without a reliable prediction on the protein (eg, splice site) are marked as p.? with their c. nomenclatures shown underneath.
Figure 4.
Figure 4.. Schematic Diagram of Rod and Cone Photoreceptors, Depicting Localization of Wild-Type and Variant PROM1
OS indicates outer segment.
See this image and copyright information in PMC

References

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