Abstract
Purpose :
Prominin 1 is a transmembrane domain glycoprotein, ubiquitously expressed in plasma membranes, namely at the protrusion of rod and cone outer segments of the retina. While dominant variants usually take a milder, slowly progressive course, recessive variants are associated with early-onset and progressive retinal degeneration. We performed a retrospective chart review of patients with pathogenic PROM1-variants to improve our understanding of this rare disease and to report two novel mutations.
Methods :
Records of 208 patients with inherited retinal disease (IRD) seen at the West Virginia University Eye Institute who had genetic testing between March 2015 and December 2020 were reviewed. We retrieved 6 patients with pathogenic PROM1 variants. Their clinical findings, retinal images, and electrodiagnostic tests were reviewed.
Results :
Pathogenic PROM1 variants were found in 6 patients (2.9%) of the genotyped IRD patients.
1. A father and 2 sons were identified with AD variant c.1117C>T. The Ganzfeld ERG was decreased in the father.
2. Two affected siblings diagnosed with cone rod dystrophy harbored two new novel PROM1 heterozygous variants: 1) c.1909C>T (p.Gln637*) and 2) c.2050C>T (p.Arg684*) and a previously reported mutation of ABCA4 c.4793 C>A (p.Ala1598Asp). Parental testing confirmed recessive inheritance. Visual acuity, visual field and ERG significantly deteriorated over 23 years.
3. The sixth patient had PROM1 variant c.642T>A(p.Tyr214*) . He displayed a Best phenotype with normal EOG and visual acuity and imaging remained stable over 4 years of follow up.
Conclusions :
We report six patients with pathogenic PROM1 mutations, characterized via genotyping, electrodiagnostic testing as well as imaging studies, corroborating reports on the general trend of AR variant taking a more severe and progressive phenotype. We also report novel AR variants of PROM1 mutation: c.1909C>T and c.2050C>T. These mutations produce premature stop codons in an extracellular domain of prominin 1, resulting in a truncated protein and loss of prominin activity. PROM1 is a key regulator of ABCA4 expression. In that regard, the presence of mutations in PROM1 and ABCA4 in our AR variants is important. Further studies are needed to elucidate the need for PROM1 in ABCA4 expression.
This is a 2021 ARVO Annual Meeting abstract.