Implications for the Diseases Chorea Acanthocytosis and McLeod Syndrome and the Proteins Chorein and XK

It is evident from the above that there are many proteins involved in membrane bending. It might be expected that in an acanthocytic condition there would be some expansion of the outer leaflet at the expense of the inner leaflet. As has been said, there could be an abnormality in lipid composition, either a phospholipid or a sterol, or there could be an abnormality in a lipid-pumping protein that has the task of

pushing lipids into the inner leaflet. There could be a defect in a membrane bending protein that enhanced inward membrane bending. It is easy to see how such a red cell abnormality, when present in the much more complex neurone, could lead to abnormalities in not only the configuration of the plasma membrane but also in the trafficking of intracellular materials or in the development of growth cones.

It is unlikely to be a coincidence that chorein is homologous in sequence to the yeast protein Vps13p (vacuolar protein sorting 13p), which, although poorly understood, is clearly associated in some way the kind of intracellular trafficking events in which membrane bending is such a prominent feature. The gene was originally identified in the baker's yeast Saccharomyces cerevisiae. Emr and others made a search for mutant strains that caused mistrafficking of a marker protein, carboxypeptidase-Y (which was in fusion with the enzyme invertase for identification purposes). Their studies revealed dozens of strains, of which Vps13p was but one [51]. The same gene, this time called SOI1, cropped up is another such genetic screen, in which Brickner and Fuller searched for yeast strains that could correct, or 'suppress' in genetic parlance, a problem in the gene Kex2p, which codes for a protein that should be trafficked to the vacuole in the cell [8]. The work on SOI1 suggested that the protein might have role in the recognition of a sequence within Kex2p that acted as a targeting label for its residence in the so-called trans-Golgi network, another subcellular membrane system within the yeast cell. The human genome contains four VPS13-like genes [66] (discussed in detail in Chapter X). Recessive changes in the related VPS13B cause the human condition known as the Cohen syndrome (MIM, 216550), in which there is psychomotor retardation with a degree of clumsiness and problems in facial appearance, the joints, the eyes and the white cells of the blood. This is a very different condition to ChAc/McLeod syndrome.

XK, changed in McLeod syndrome, is similar to a gene from the nematode Caenorhabditis elegans. Mutations in this gene, ced-8, cause a problem is so-called 'programmed cell death', or apoptosis, the mechanism by which cells that are no longer required (for one reason or another) are cleanly tidied away [62]. These genes (ced-8. XK) appear to code for a plasma membrane protein that could act as a channel, but what the channel transports is an unanswered question.

Fig. 4 Three-dimensional ultrastructure of erythrocyte membrane skeletons in McLeod syndrome revealed by the quick-freezing and deep-etching replica method. (a) Schematic representation of protrusions of acanthocytic erythrocytes [inset in a-(I)]. By sandwich-splitting between two silane-glutaraldehyde-coated glass slides, a protrusion of the acanthocyte [asterisk in a-(II)] is easily turned inside-out [asterisk in a-(III)], enabling us to directly observe membrane skeletal structures with the quick-freezing and deep-etching replica method [65] Stereo-pictures were routinely obtained by a pair of pictures of the replica membranes with ± 5°. (b) Stereo-picture of normal erythrocyte membrane skeletons. Compact membrane skeletons can be seen on the lipid cell membrane. (c, d) Three-dimensional membrane skeletons of acanthocytes from McLeod syndrome patients are viewed as stereo-pictures. In some acanthocytes, loosely arranged membrane skeletons [arrows in (c)] are focally observed. Other completely inside-out protrusions [arrows in (d)] have less filamentous structures, whereas mixed filamentous and granular structures still remain around the protrusions. Bar; 500 nm

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