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Genetic Analysis of Choroideremia-Related Rab Escort Proteins

Year: 2025
Type: article
Abstract: gene, which encodes Rab escort protein 1 (REP-1). In humans and mice, the Rab escort protein (REP) family consists of two members, REP-1 and REP-2, with REP-2 hypothesized to compensate for REP-1 deficiency in tissues outside the eye in choroideremia. In this study, we conducted a systematic mutational analysis of the mouse orthologs of REP-1 and REP-2. Blood analyses revealed metabolic abnormalities in the mutant mice deficient for REP-1, resembling the systemic metabolic disturbances observed in individuals with choroideremia, such as altered lipid and hemoglobin metabolism. We also observed an elevation in systemic inflammatory biomarkers in these mutant mice. Interestingly, these systemic abnormalities emerged before retinal degeneration became detectable in REP-1-deficient mice. Transcriptomic analysis of retinas isolated from REP-1 deficient mice revealed enrichment of proinflammatory signaling pathways. These results suggest important similarities between choroideremia and some forms of retinitis pigmentosa. While engineered loss of REP-2 alone caused no detectable phenotypic changes, dual deficiency in REP-1 and REP-2 resulted in lethality under both in vivo and in vitro conditions. Our findings offer novel insights into REPs and deepen our understanding of choroideremia, which may contribute to the development of new treatments for this genetic condition.
DOI: 10.3390/ijms26083636
Authors: Zhuo Xing, Fuguo Wu, Eduardo Cortes-Gomez, Annie Pao, Lingqiu Gao, Avrium Douglas, Yichen Li, Joseph A. Spernyak, G. William Wong, Prashant K. Singh, Jianmin Wang, Song Liu, Yasmin Thanavala, Ian M. MacDonald, Xiuqian Mu, Y. Eugene Yu
Institutions: Roswell Park Comprehensive Cancer Center, University at Buffalo, State University of New York, Cleveland Clinic, Cleveland Clinic Research, Johns Hopkins University, Johns Hopkins Medicine, Université de Montréal
Language: English
Subfield: Ophthalmology
Field: Medicine
Open Access status: gold
Estimated APC paid: $3,499
Awards: Regulation of mRNA decay in retinal development and maintenance, Mechanisms of Down syndrome-associated swallowing dysfunction in mouse models, Acquisition of a 7T MR scanner for Translational Imaging Research at Roswell Park, Epigenetics of Down Syndrome, Mutational analysis to understand the role of CHML in developmental regression, Director Genomics Shared Resource, Regulatory mechanisms for retinal ganglion cell genesis, Initiative for Maximizing Student Development at University at Buffalo, Generation and analysis of new mouse models to determine novel therapeutic targets for Down syndrome-associated cognitive deficits
OpenAlex ID: W4409435457
FWCI: 0.758
Cites: 66
Cited by: 1
Related to: 10