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choroideremia

Saturday 3 June 2006

Choroideremia is an X-linked form of retinitis pigmentosa characterized by degeneration of the retinal pigment epithelium and the adjacent choroid and retinal photoreceptor-cell layers.

Physiopathology

The gene mutated in choroideremia was identified as that encoding component A of the Rab geranylgeranyltransferase, also designated Rab escort protein 1 (REP-1).

This protein and its isoform, Rab escort protein 2 (REP-2), are essential for the modification of the Rab GTPases by hydrophobic isoprenoid moieties that mediate their membrane association.

The limited phenotype lies in the overlapping patterns of expression and substrate specificities of the isoforms of the Rab escort protein; REP-2 is most likely capable of compensating for the loss of activity of REP-1 in most tissues.

However, the small GTPase Rab27 that is expressed in the retinal-cell layers subject to degeneration in choroideremia preferentially interacts with the REP-1 isoform. Therefore, disturbed function of Rab27 may lead to a specific membrane-transport abnormality in the affected retinal cells.

Despite the fact that the protein machinery involved in the docking and fusion of transport vesicles has been characterized extensively in the past 10 years, there are only two diseases in humans in which the genetic defect has been traced to this highly conserved machinery.

Both these diseases, choroideremia and X-linked nonspecific mental retardation, involve mutations in the auxiliary protein factors controlling the membrane association of the Rab GTPases.

References

- Olkkonen VM, Ikonen E. Genetic defects of intracellular-membrane transport. N Engl J Med. 2000 Oct 12;343(15):1095-104. PMID: 11027745

- van den Hurk JAJM, Hendriks W, van de Pol DJR, et al. Mouse choroideremia gene mutation causes photoreceptor cell degeneration and is not transmitted through the female germline. Hum Mol Genet 1997;6:851-858.