A practical diagnostic test for choroideremia

MacDonald, Ian M.; Mah, Dean Y.; Ho, Y. K.; Lewis, Richard A.; Seabra, Miguel C.

doi:10.1016/s0161-6420(98)99031-5

Cited by 66 publications

(47 citation statements)

References 13 publications

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“…Consistent with the observation that the lymphocytes of many affected males lack REP1 [MacDonald et al, 1998], our patients were mainly affected by mutation types that abolish the synthesis of the CHM gene product. In most cases, we found aberrant mRNA species that lead to truncated peptides in vitro (Fig.…”

Section: Genetic Study Of Affected Malessupporting

confidence: 91%

Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with rab geranylgeranyl transferase

et al. 2011

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Choroideremia (CHM), an X-linked degeneration of the retinal pigmented epithelium (RPE), photoreceptors, and choroid, ultimately leads to blindness. It is caused by loss-of-function of the CHM gene product, the Rab escort protein 1 (REP1) that is involved, together with its homologue REP2, in prenylation of Rab GTPases, key regulators of intracellular vesicular traffic. Here, we report the molecular characterization of 20 unrelated Italian families affected by CHM. We identified 19 different mutations, nine of which are new. In most cases, we analyzed the effect of the mutations at the mRNA level. Furthermore, we demonstrated, by in vitro trancription/translation assays, that the mutated mRNAs produced truncated proteins in all cases but one. In fact, we also identified a novel REP1 missense variant (c.1520A>G; p.H507R) associated to CHM. Thus far, only two other CHM-associated missense mutations have been identified, one of which was a splicing alteration. We investigated the impact of the p.H507R amino acid change on REP1 structure and function, thus providing the first experimental demonstration that correlates a missense mutation in CHM with a functional impairment of REP1. Overall, our results indicate that the REP1-Rab geranyl-geranyl transferase interaction and consequently REP1-mediated Rab prenylation is essential for RPE and photoreceptor function.

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Section: Genetic Study Of Affected Malessupporting

confidence: 91%

Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with rab geranylgeranyl transferase

et al. 2011

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“…The molecular basis for CHM is mutation in the gene encoding Rab escort protein-1 (REP-1) (Cremers et al, 1990;Merry et al, 1992;van Bokhoven et al, 1994). To date, mainly loss of function mutations have been identi®ed in CHM patients (MacDonald et al, 1998). Facility of clinical diagnosis and greater understanding of molecular cause in CHM, however, have not yet led to the treatment of this serious retinal disease.…”

Section: Introductionmentioning

confidence: 99%

Macular Pigment and Lutein Supplementation in Choroideremia

Duncan

Alemán

Gardner

et al. 2002

Experimental Eye Research

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“…Not only is this a monogenetic disease, but CHM is relatively simple to diagnose, compared with other inherited blinding diseases, greatly facilitating the identification of the target patient population for drug treatment studies (MacDonald et al 1998); additionally, retinal degeneration develops slowly and does not begin until the second decade of life, providing a relatively large time frame for therapeutic intervention (Freund et al 2016). While mutations in the CHM gene include full deletions, partial deletions, deletion/insertions, splice site mutations, and nonsense mutations, immunoblot analysis of protein from white blood cells of CHM patients shows that most patients lack the REP-1 gene product (MacDonald et al 1998). Despite an understanding of the genetic cause of CHM, development of a gene therapy has been delayed by the limited availability of animal models.…”

Section: Choroideremia Gene Therapymentioning

confidence: 99%