Expression of Rab Prenylation Pathway Genes and Relation to Disease Progression in Choroideremia

Abstract

Choroideremia results from the deficiency of Rab Escort Protein 1 (REP1), encoded by CHM, involved in the prenylation of Rab GTPases. Here, we investigate whether the transcription and expression of other genes involved in the prenylation of Rab proteins correlates with disease progression in a cohort of patients with choroideremia.Methods: Rates of retinal pigment epithelial area loss in 41 patients with choroideremia were measured using fundus autofluorescence imaging for up to 4 years. From lysates of cultured skin fibroblasts donated by patients (n = 15) and controls (n = 14), CHM, CHML, RABGGTB and RAB27A mRNA expression, and REP1 and REP2 protein expression were compared. Results:The central autofluorescent island area loss in patients with choroideremia occurred with a mean half-life of 5.89 years (95% confidence interval [CI] = 5.09-6.70), with some patients demonstrating relatively fast or slow rates of progression (range = 3.3-14.1 years). Expression of CHM mRNA and REP1 protein were significantly decreased in all patients. No difference in expression of CHML, RABGGTB, RAB27A, or REP2 was seen between patients and controls. No correlation was seen between expression of the genes analyzed and rates of retinal degeneration. Non-sense induced transcriptional compensation of CHML, a CHM-like retrogene, was not observed in patients with CHM variants predicted to undergo non-sense mediated decay.Conclusions: Patients with choroideremia, who are deficient for REP1, show normal levels of expression of other genes involved in Rab prenylation, which do not appear to play any modifying role in the rate of disease progression.Translational Relevance: There remains little evidence for selection of patients for choroideremia gene therapy based on genotype.

Protective effects of intrathecal injection of AAV9-RabGGTB-GFP+ in SOD1G93A mice

“…As an inhibitor of Rab-prenylation, psoromic acid has been found to be effective in the treatment of osteoporosis (Deraeve et al, 2012). Finally, no obvious correlation was found between expression of Rab prenylation pathway genes and the disease progression in choroideremia (Fry et al, 2021). However, to the best of our knowledge, there has been no research on the relationship between ALS and RabGGTase and its related treatment.…”

Choroideremia: The Endpoint Endgame

“…Classically, there is progressive degeneration of the retina and choroid starting in the mid-periphery and extending both centripetally and anteriorly [ 6 , 7 ], as illustrated in Figure 2 . Other genes involved in Rab prenylation do not appear to play any modifying role in the rate of disease progression [ 8 ]. In advanced disease, the fovea becomes involved ( Figure 3 ).…”