Phosphatidylserine (PtdSer) is a phospholipid that is abundant in eukaryotic plasma membranes. An ATP-dependent enzyme called flippase normally keeps PtdSer inside the cell, but PtdSer is exposed by the action of scramblase on the cell's surface in biological processes such as apoptosis and platelet activation. Once exposed to the cell surface, PtdSer acts as an 'eat me' signal on dead cells, and creates a scaffold for blood-clotting factors on activated platelets. The molecular identities of the flippase and scramblase that work at plasma membranes have long eluded researchers. Indeed, their identity as well as the mechanism of the PtdSer exposure to the cell surface has only recently been revealed. Here, we describe how PtdSer is exposed in apoptotic cells and in activated platelets, and discuss PtdSer exposure in other biological processes.

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Exposure of phosphatidylserine on the cell surface.

Similar to apoptosis of nucleated cells, suicidal erythrocyte death or eryptosis is characterized by cell shrinkage, membrane blebbing and membrane phospholipid scrambling with phosphatidylserine exposure at the cell surface. Signaling of eryptosis involves formation of prostaglandin E2 with subsequent activation of cation channels and Ca2+-entry and/or release of platelet activating factor (PAF) with subsequent activation of sphingomyelinase and formation of ceramide. Ca2+ and ceramide stimulate cell membrane scrambling. Ca2+ further activates Ca2+-sensitive K+-channels leading to cellular KCl loss and cell shrinkage and stimulates the protease calpain resulting in degradation of the cytoskeleton. Injuries triggering eryptosis may similarly compromise survival of nucleated cells. The case is made that analysis of enhanced eryptosis may direct to the pathophysiology of systemic disease. Examples presented include drug side effects, sepsis, haemolytic uremic syndrome, Wilson´s disease, phosphate depletion and a rare condition caused by a mutation in GLUT1 turning the carrier into a cation channel.

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Eryptosis, a Window to Systemic Disease

McLeod syndrome is caused by mutations of XK, an X-chromosomal gene of unknown function. Originally defined as a peculiar Kell blood group variant, the disease affects multiple organs, including the nervous system, but is certainly underdiagnosed. We analyzed the mutations and clinical findings of 22 affected men, aged 27 to 72 years. Fifteen different XK mutations were found, nine of which were novel, including the one of the eponymous case McLeod. Their common result is predicted absence or truncation of the XK protein. All patients showed elevated levels of muscle creatine phosphokinase, but clinical myopathy was less common. A peripheral neuropathy with areflexia was found in all but 2 patients. The central nervous system was affected in 15 patients, as obvious from the occurrence of seizures, cognitive impairment, psychopathology, and choreatic movements. Neuroimaging emphasized the particular involvement of the basal ganglia, which was also detected in 1 asymptomatic young patient. Most features develop with age, mainly after the fourth decade. The resemblance of McLeod syndrome with Huntington's disease and with autosomal recessive chorea-acanthocytosis suggests that the corresponding proteins--XK, huntingtin, and chorein--might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.

McLeod neuroacanthocytosis: genotype and phenotype.

The term acanthocytosis is derived from the Greek for "thorn" and is used to describe a peculiar spiky appearance of erythrocytes Acanthocytosis is found to be associated with at least three hereditary neurological disorders that are generally referred to as neuroacanthocytosis Abetalipoproteinaemia is an autosomal recessive condition, characterised by absence of serum apolipoprotein B containing lipoproteins leading to fat intolerance and fat-soluble vitamin deficiency This results in a progressive spinocerebellar ataxia with peripheral neuropathy and retinitis pigmentosa Chorea-acanthocytosis is also an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysphagia, dysarthria, areflexia, seizures and dementia Some of its features, including choreic movements, peripheral neuropathy with areflexia, elevated serum creatine kinase levels and myopathy are shared by another form of neuroacanthocytosis, McLeod syndrome Patients affected by this X-linked disorder also show abnormal expression of Kell blood group antigens and a permanent haemolytic state In addition to these cases, acanthocytosis is occasionally associated with other neurological disorders, such as Hallervorden-Spatz disease For each of the neuroacanthocytosis syndromes we review the main clinical features and their molecular bases The recent molecular genetics findings are the first step towards the understanding of the pathogenetic mechanisms and eventually the search for effective treatments

Clinical features and molecular bases of neuroacanthocytosis

Red blood cell blood group antigens: Structure and function

Among the movement disorders associated with acanthocytosis, McLeod syndrome (McKusick 314850) is the one that is best characterized on the molecular level. Its defining feature is low reactivity of Kell erythrocyte antigens. This is due to absence of membrane protein KX that forms a complex with the Kell protein. KX is coded for by the XK gene on the X-chromosome. We present six males (aged 29 to 60 years), with proven XK mutations, to discuss the chorea associated with McLeod syndrome. The movement disorder commonly develops in the fifth decade and is progressive. It affects the limbs, the trunk and the face. In addition to facial grimacing, involuntary vocalization can be present. In early stages there may only be some restlessness or slight involuntary distal movements of ankles and fingers. Lip-biting and facial tics seem more common in autosomal recessive choreoacanthocytosis linked to chromosome 9. This, together with the absence of dysphagia in McLeod syndrome, may help in differential diagnosis. Recent findings suggest a role for the endothelin system of the striatum in the pathogenesis of McLeod syndrome.

Wolfgang von Kalckreuth

Papers

McLeod neuroacanthocytosis: genotype and phenotype.

The chorea of McLeod syndrome