Skip Navigation LinksHome > May 2014 - Volume 21 - Issue 3 > Abnormal red cell features associated with hereditary neurod...
Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000035
ERYTHROID SYSTEM AND ITS DISEASES: Edited by Narla Mohandas

Abnormal red cell features associated with hereditary neurodegenerative disorders: the neuroacanthocytosis syndromes

De Franceschi, Luciaa; Bosman, Giel J.C.G.M.b; Mohandas, Narlac

Free Access
Article Outline
Collapse Box

Author Information

aDepartment of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy

bDepartment of Biochemistry, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

cRed Cell Physiology Laboratory, New York Blood Center, New York, New York, USA

Correspondence to Lucia De Franceschi, MD, Department of Medicine, University of Verona and AOUI, Policlinico GB Rossi, P.le L Scuro, 10; 37134 Verona, Italy. Tel: +39 0458124918; fax: +39 0458027473; e-mail: lucia.defranceschi@univr.it

Collapse Box

Abstract

Purpose of review

This review discusses the mechanisms involved in the generation of thorny red blood cells (RBCs), known as acanthocytes, in patients with neuroacanthocytosis, a heterogenous group of neurodegenerative hereditary disorders that include chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS).

Recent findings

Although molecular defects associated with neuroacanthocytosis have been identified recently, their pathophysiology and the related RBC abnormalities are largely unknown. Studies in ChAc RBCs have shown an altered association between the cytoskeleton and the integral membrane protein compartment in the absence of major changes in RBC membrane composition. In ChAc RBCs, abnormal Lyn kinase activation in a Syk-independent fashion has been reported recently, resulting in increased band 3 tyrosine phosphorylation and perturbation of the stability of the multiprotein band 3-based complexes bridging the membrane to the spectrin-based membrane skeleton. Similarly, in MLS, the absence of XK-protein, which is associated with the spectrin–actin–4.1 junctional complex, is associated with an abnormal membrane protein phosphorylation state, with destabilization of the membrane skeletal network resulting in generation of acanthocytes.

Summary

A novel mechanism in generation of acanthocytes involving abnormal Lyn activation, identified in ChAc, expands the acanthocytosis phenomenon toward protein–protein interactions, controlled by phosphorylation-related abnormal signaling.

Back to Top | Article Outline

INTRODUCTION

In the 1960s Irving M. Levine and Critchley separately reported a new hereditary neurological disorder characterized by hyporeflexia, mild muscle weakness and atrophy associated with thorny red cells, acanthocytes (Fig. 1) [1–4]. This disorder was described as neuroacanthocytosis based upon the clinical phenotype [3,4]. Today, neuroacanthocytosis syndromes consist of chorea-acanthocytosis (ChAc), McLeod syndrome (MLS), Hungtington's disease like-2 (HDL2) and pantothenate-kinase-associated neurodegeneration (PKAN) [5]. Acanthocytes are one of the biological hallmarks of neuroacanthocytosis. The analysis of the abnormal red blood cells (RBCs) from neuroacanthocytosis patients, to define the mechanistic basis for the red cell phenotype, will further help our understanding of the pathogenesis of neuroacanthocytosis.

FIGURE 1
FIGURE 1
Image Tools
Back to Top | Article Outline

NORMAL RED CELL MEMBRANE ORGANIZATION AND RED CELL SHAPE

The study of human RBCs has led to the development of a general model of RBC membrane organization based on the functional cross-talk between the membrane lipid bilayer, the integral membrane proteins such as band 3 and the peripheral proteins such as spectrins and actin (Fig. 2). The RBC membrane is anchored to the membrane skeleton network through the band 3-based bridges formed by multiprotein complexes involving ankrin and protein 4.1 (or junctional complex) (Fig. 2) [6–14]. The study of hereditary RBC disorders has provided insight into the RBC membrane organization and function. Mutations in proteins involved in the vertical interactions such as band 3 or ankyrin with membrane skeleton result in loss of membrane surface area and generation of spherocytes as in patients with hereditary spherocytoses. However, mutations in proteins affecting lateral interactions such as spectrin dimer–dimer or spectrin–actin–protein 4.1 interactions result in loss of RBC membrane mechanical stability and generation of elliptocytes, as in patients with hereditary elliptocytosis (Fig. 2) [8].

FIGURE 2
FIGURE 2
Image Tools
Box 1
Box 1
Image Tools

Although these RBC shape abnormalities have been related to genes encoding for membrane and skeletal proteins, abnormal RBC morphology has been also described in diseases primarily affecting the lipid bilayer such as abetalipoproteinemia and spur cell anemia. Hypercholesterolemic mice generated by inactivation of SR-BI (SR-BI−/−), a gene encoding the high-density lipoprotein receptor, have macrocytic anemia with abnormal circulating RBCs and large membrane-enclosed intracellular inclusions [15]. The severity of the SR-BI−/− hematological phenotype was related to the cellular cholesterol content, suggesting that cholesterol is important in erythroid maturation and in generation of normal RBCs [15]. In patients with abetalipoproteinemia or hypobetalipoproteinemia, the deficiency of apolipoprotein B is associated with acanthocytosis and neurological manifestation but without movement disorders such as those seen in the neuroacanthocytosis syndromes [5]. Changes in the composition of RBC membrane lipids have been also associated with the generation of acanthocytes in spur cell anemia, which occurs in patients with advanced liver failure and resolves after liver transplantation [16].

In the present review, we focus on acanthocytosis in neuroacanthocytosis, summarizing the recent advances in our knowledge on the mechanisms underlying the generation of acanthocytes in neuroacanthocytosis syndromes.

Back to Top | Article Outline

CHOREA-ACANTHOCYTOSIS

Chorein is the 360-kDa protein product of the VPS13A gene (chromosome 9), mutations of which are associated with the autosomal recessive disorder of ChAc [5,17,18]. Chorein is present in mature RBCs and is partially or completely absent in ChAc RBCs [19]. At the present, the lack of information regarding the biochemical structure and interactions of chorein with other proteins makes it difficult to formulate a hypothesis on its role in RBC homeostasis (Table 1) [20–24,25▪▪,26–31,32▪,33–39].

Table 1
Table 1
Image Tools

In ChAc RBCs, electron microscopic studies have revealed a heterogeneous distribution of the membrane skeleton characterized by condensated cytoskeletal structures around protrusions and less filamentous structure in some large patches of the membrane (Table 1) [21]. Although no major abnormalities in RBC membrane protein composition and abundance have been observed in ChAc RBCs, an increased amount of Nε (γ-glutamyl) lysine isopeptide associated with RBC membrane was reported in a small number of ChAc patients (Table 1) [24,40]. Transglutaminase 2 catalyzes the organization of multicomplex protein cross-linked by the Nε (γ-glutamyl) lysine isopeptide. The main protein involved is band 3 through its Gln-30 residues, together with bridging proteins such as ankyrin or protein 4.1 and skeletal proteins such as spectrins [40–42]. A recently described enrichment of actin in the Triton-soluble fraction of ChAc RBCs supports earlier data showing a perturbation of the skeletal network and possible instability in bridging band 3-based multiprotein complexes in the absence of chorein [43]. This finding is also supported by the observation of a reduced response of ChAc red cells to drugs inducing endovesicles [25▪▪] In addition, a reduced RBC K+ content has been described in ChAc patients [20]. These data suggest a more complex scenario in ChAc that might involve posttranslational modifications such as phosphorylation affecting protein–protein interactions between membrane proteins and skeletal network. Indeed, recent in-vitro studies have shown that an imbalance between phosphatase-kinase activities might result in an altered band 3 phosphorylation state [11,12,44]. This might affect the stability of the complexes involving band 3, bridging the membrane to the skeletal network [22,23,45] (Fig. 2). In RBCs, Syk, a Src-related kinase, and Lyn, a Src kinase, are part of the signaling pathway targeting band 3 and affecting its protein interactions [46]. In ChAc RBCs, we recently studied the tyrosine (Tyr)-phosphoproteome and found an increased Tyr-phosphorylation state of several membrane proteins, including band 3, compared with controls [23]. We observed an increased phosphorylation of the Tyr-904 residue on band 3, which is a functional target of Lyn, but not of the Tyr-8 residue that is a target of Syk (Fig. 2). We demonstrated an abnormal Lyn activation independent from its canonical pathway through the primary Syk activation. We then postulated that the ChAc-associated alterations in RBC membrane protein organization are the result of increased Tyr-phosphorylation state leading to an altered linkage of band 3 to the junctional complexes, and generation of acanthocytes (Fig. 2). This conclusion is also supported by the recent observations that the blood of mice with constitutively active Lyn contains acanthocytes [47▪▪]. To date, there are not consistent data implicating an altered membrane lipid composition in acanthocytosis in ChAc [20].

ChAc presents clinically in young adulthood [5,48]. An increased serum creatine kinase may precede the neurological symptoms, and sometimes is associated with hepatosplenomegaly [5,48]. At the present, 120 mutations in the VPS13A gene of various types have been described, resulting in low or absent synthesis of chorein or normal expression of a functionally defective protein [17,49].

VSP13A is a member of the VPS13 family (VPS13A–D) [50,51]. A comparison of the human gene sequence with those of other organisms has shown large similarities of the human protein VPS13A with the yeast Vps13p protein and the Dictyostelium discoideum TipC proteins, whereas the other VSP13 genes seem to result from more recent evolutionary events [52,53]. Vps13p protein is involved in trafficking of various transmembrane proteins, in particular in the recruitment of three membrane proteins to the trans-Golgi network: Kex2p, a Golgi-endoprotease; Ste13p, a dipeptidyl aminopeptidase; and Vps10p, a cargo-sorting receptor, which delivers the cargo enzymes to the prevacuolar compartment similar to human late endosome [54–56].

Human chorein has been recently cloned and expressed in various cell lines [50]. Confocal microscopy showed a cytoplasmic localization of chorein in a vesicular-like pattern [50].

A mouse model with a VPS13A deletion showed reduced expression of chorein and production of truncated protein (Table 2[57–61,62▪,63–66]). These ChAc mice developed a mild, late-onset motor disturbance with late adult onset and acanthocytes with increased osmotic fragility; however, no functional studies have been reported [57,58].

Table 2
Table 2
Image Tools
Back to Top | Article Outline

McLEOD SYNDROME

The XK protein (444 amino acid residues, containing the Kx antigen) is the membrane protein associated with MLS, which is an X-linked form of neuroacanthocytosis [26–28,67]. The XK protein is predicted to have 10 transmembrane domains with structural characteristics of a membrane transporter protein, but its function is yet to be defined. In the RBC membrane, the XK protein (50 kDa) is covalently linked to the Kell glycoprotein (93 kDa) by a single disulfide bond (XK Cys347–Kell Cys72) and is part of the multiprotein 4.1 junctional complex (Fig. 2) [29,68,69]. In MLS RBCs, truncation of the XK protein is associated with reduced expression of the Kell blood group antigen and a compensated hemolytic anemia [70–73].

Functional studies of MLS RBCs have shown a reduced resistance to mechanical stress and increased RBC density associated with reduced RBC K+ content (Table 1) [21,30,31,74–76]. Electron microscopic studies demonstrate a heterogeneous distribution of the RBC membrane skeleton, mainly present in the denser RBC fraction containing acanthocytes [20,21,26].

The abnormal Tyr-phosphorylation state of some membrane proteins in MLS RBCs indicates once more an involvement of posttranslational modifications and/or disturbed intracellular signalling in acanthocyte formation (Table 1) [34,76]. Preliminary investigations of the RBC membrane phosphoproteome showed that the RBC membrane Tyr-phosphorylation pattern was significantly different in MLS RBCs compared with controls. More specifically, an increased Tyr-phosphorylation state of ankyrin and protein 4.1 was found in MLS RBCs [32▪]. In this regard, it may be relevant that changes in protein 4.1 phosphorylation state affect RBC membrane mechanical stability [77]. Furthermore, RBCs of protein 4.1 knockout mice (4.1−/−) show a perturbation of the RBC membrane multiprotein complexes involving glycophorin C, XK, Duffy and Rh proteins [78]. In MLS, it is likely that besides a reduction of XK–Kell complex, multiple factors contribute to an alteration of RBC membrane stability, such as changes in protein phosphorylation state, resulting in a destabilization of the skeletal network with generation of acanthocytes (Fig. 2).

MLS is found worldwide, and has a variable clinical presentation, with a mean age of onset between 30 and 40 years. It is mainly characterized by chorea, generalized seizures, neuropsychiatric abnormalities, cardiac myopathy, mild hemolytic anemia with acanthocytosis and hepatosplenomegaly [5,71]. The majority of the 28 identified XK mutations comprise small and large (5 Mb) deletions, frameshift and nonsense mutations, resulting in an absent or truncated XK protein [5,71]. Two missense mutations in the XK gene and one single nucleotide mutation in an intron near the splice junction have been reported as causing MLS with a milder clinical phenotype [5,26]. The XK protein is ubiquitously expressed [5]. Phylogenetic analysis showed that XK protein is a member of the XK family of proteins, containing XPLAC and XTEST proteins that share 37% and 31% homology, respectively, with XK. These proteins have a common domain with a consensus sequence that shares homologies with the ced-8 protein from the nematode Caernorhabditis elegans[29,79]. Ced-8 is involved in regulation of apoptosis in C. elegans, but it is not known whether XK plays a similar role in RBCs, erythoid precursors or in neuronal cells.

Back to Top | Article Outline

HUNTINGTON DISEASE-LIKE 2

Acanthocytes have been observed in patients with Huntington's disease-like 2 (HDL2), an autosomal dominant neurodegenerative disorder resembling Huntington's disease. In HDL2, acanthocytosis-specific changes in membrane organization are suggested by the presence of band 3 breakdown products [80] and by the in-vitro production of vesicles that are different from the vesicles of control RBCs [34]. Preliminary RBC membrane proteomic analysis suggested that proteasome components and small G proteins were increased in HDL2 patients compared with controls [34]. Recently, it has been reported that RBCs from mice genetically lacking the small G protein Rac GTPase have a perturbation of dynamic regulation of the RBC membrane skeletal network [81]. This suggests a possible involvement of small G proteins in membrane skeletal rearrangement in acanthocytosis in HDL2 (Table 2).

HDL2 is caused by a CAG/CTG expansion mutation in exon 2A of the junctophilin-3 gene (JPH3) on chromosome 16q24.3 [82]. HDL2 has only been identified in individuals of African descent, in mid-life, with involuntary movements, neuropsychiatric symptoms and dementia [82,83]. Postmortem studies of HDL2 patients have shown intranuclear aggregates that were labeled with antiubiquitin antibodies and with anti1C2 antibody against long polyglutamine tracts in striatum and cortex, similar to those observed in Huntington's disease [80,84]. To date, it is not known how these aggregates might contribute to the neurological damage of HDL2. Mice genetically lacking the JPH3 protein present a very mild phenotype, whereas cognitive and motor deficiencies were only present when both JPH3 and JPH4 genes were knocked out simultaneously, suggesting a more complex pathogenesis of HDL2 disease than the loss of JPH3 function (Table 2) [59]. A recently developed bacterial artificial chromosome-transgenic mouse model for HDL2 [60] shows age-dependent motor deficiency and a pathological HDL2 neuronal phenotype, but no data are reported on RBC features (Table 2).

Back to Top | Article Outline

PANTOTHENATE KINASE-ASSOCIATED NEURODEGENERATION

Acanthocytes are also found in approximately 10% of the pantothenate kinase-associated neurodegeneration (PKAN) patients [35]. Data from preliminary proteomic experiments indicate a PKAN RBC membrane protein composition different from both control and other neuroacanthocytosis RBCs (Bosman et al., unpublished data). A recent study has shown reduced response of acanthocytic PKAN RBCs but not of normal shaped PKAN RBCs to drug-induced endovesicle formation [25▪▪]. We know of no other detailed studies on RBCs from PKAN patients. PKAN is an autosomal recessive disease caused by mutations in the human PANK2 gene on chromosome 20p13 encoding for the pantothenate kinase 2 protein isoforms, which are localized in mitochondria [36–38,85]. PANK2 is a key enzyme in the biosynthesis of coenzyme A (CoA), which is important for energy metabolism, and fatty acid and neurotransmitter metabolism. A founder mutation effect has been described in the Netherlands [39]. The typical onset of PKAN is in childhood. A specific pattern of brain iron accumulation in the globus pallidus results in the eye-of-the-tiger pattern on magnetic resonance imaging [35,36].

Down-regulation of PANK2 expression in vitro in different cell lines resulted in reduced cell growth related to iron deficiency without mitochondrial iron deposition, associated with a significant increase in ferroportin [86]. As ferroportin is involved in iron homeostasis through the hepcidin–ferroportin pathway and might be also important in regulation of brain iron levels, ferroportin has been suggested to play a role in the altered iron transport to brain observed in PKAN patients [86]. Mice genetically lacking PANK2 (pank2-/-) show retinal degeneration, mitochondrial neuronal dysfunction and male infertility, but no dystonia and only minor alterations in the basal ganglia (Table 2) [61,62▪]. Normal mice treated with either pantothenate kinase inhibitor or on a diet without pantothenic acid develop movement disorders and male infertility but show no iron accumulation in the basal ganglia (Table 2) [63,64]. Thus, to date, mouse models seem to be of limited used in the study of PANK. However, three human mutations of PANK2 have been expressed in the fbl gene in Drosophila melanogaster, corresponding to the human PANK2 gene. In these flies, the decrease in pantothenate kinase activity correlated with the severity of the phenotype (Table 2). This represents an interesting model to study PKAN, even if the observed neurodegeneration was not associated with neuronal iron accumulation [65,66].

Back to Top | Article Outline

CONCLUSION

The significance of the combination of neuronal degeneration in the basal ganglia with the formation of acanthocytes in patients with various neuroacanthocytosis syndromes is still far from being understood. Recent proteomic and functional data on RBC from ChAc and MLS patients confirm previous evidence on the central role of band 3 in acanthocyte formation, and expand the acanthocytosis phenomenon toward protein–protein interactions, controlled by phosphorylation-related signaling [34]. This opens new diagnostic possibilities, and suggests that, in principle, signaling-based intervention is possible. At present, the clinical approach to the neuroacanthocytosis syndromes is essentially symptomatic with a combination of medical therapy to reduce involuntary movements and/or neurosurgery with deep brain stimulation or ablative procedures, although the latter remains to be validated in a large cohort of patients [87]. In view of the specific and characteristic association of acanthocytosis with neurodegeneration, RBCs constitute a promising target for future mechanistic and functional studies.

Back to Top | Article Outline

Acknowledgements

The work of L.D.F. and G.B. described in this manuscript is supported by the Advocacy for Neuroacanthocytosis Patients (John Grooms Working with Disabled people), Carl H. and Elizabeth S. Pforzheimer III (New York), Ginger and Glenn Irvine (London) and Telethon grant (GPP07007 and GPP13005, LDF). We thank Dr Ruth H. Walker and Prof. Adrian Danek for revision of the manuscript on neurological aspects of NA and Dr Carlo Tomelleri for the images on normal and ChAc RBCs.

Back to Top | Article Outline
Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Back to Top | Article Outline

REFERENCES

1. Estes JW, Morley TJ, Levine IM, Emerson CP. A new hereditary acanthocytosis syndrome. Am J Med. 1967; 42:868–881.

2. Levine IM, Estes JW, Looney JM. Hereditary neurological disease with acanthocytosis. A new syndrome. Arch Neurol. 1968; 19:403–409.

3. Critchley EM, Clark DB, Wikler A. Acanthocytosis and neurological disorder without betalipoproteinemia. Arch Neurol. 1968; 18:134–140.

4. Critchley EM, Clark DB, Wikler A. An adult form of acanthocytosis. Trans Am Neurol Assoc. 1967; 92:132–137.

5. Jung HH, Danek A, Walker RH. Neuroacanthocytosis syndromes. Orphanet J Rare Dis. 2011; 6:68

6. Anong WA, Franco T, Chu H, et al. Adducin forms a bridge between the erythrocyte membrane and its cytoskeleton and regulates membrane cohesion. Blood. 2009; 114:1904–1912.

7. Perrotta S, Borriello A, Scaloni A, et al. The N-terminal 11 amino acids of human erythrocyte band 3 are critical for aldolase binding and protein phosphorylation: implications for band 3 function. Blood. 2005; 106:4359–4366.

8. Mohandas N, Gallagher PG. Red cell membrane: past, present, and future. Blood. 2008; 112:3939–3948.

9. Andolfo I, Alper SL, De Franceschi L, et al. Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1. Blood. 2013; 121:3925–3935.

S3921–S3912


10. Andolfo I, Alper SL, Delaunay J, et al. Missense mutations in the ABCB6 transporter cause dominant familial pseudohyperkalemia. Am J Hematol. 2013; 88:66–72.

11. Iolascon A, De Falco L, Borgese F, et al. A novel erythroid anion exchange variant (Gly796Arg) of hereditary stomatocytosis associated with dyserythropoiesis. Haematologica. 2009; 94:1049–1059.

12. Pantaleo A, Ferru E, Giribaldi G, et al. Oxidized and poorly glycosylated band 3 is selectively phosphorylated by Syk kinase to form large membrane clusters in normal and G6PD-deficient red blood cells. Biochem J. 2009; 418:359–367.

13. De Franceschi L, Olivieri O, Miraglia del Giudice E, et al. Membrane cation and anion transport activities in erythrocytes of hereditary spherocytosis: effects of different membrane protein defects. Am J Hematol. 1997; 55:121–128.

14. De Franceschi L, Bachir D, Galacteros F, et al. Oral magnesium pidolate: effects of long-term administration in patients with sickle cell disease. Br J Haematol. 2000; 108:284–289.

15. Holm TM, Braun A, Trigatti BL, et al. Failure of red blood cell maturation in mice with defects in the high-density lipoprotein receptor SR-BI. Blood. 2002; 99:1817–1824.

16. Allen DW, Manning N. Cholesterol-loading of membranes of normal erythrocytes inhibits phospholipid repair and arachidonoyl-CoA:1-palmitoyl-sn-glycero-3-phosphocholine acyl transferase. A model of spur cell anemia. Blood. 1996; 87:3489–3493.

17. Rampoldi L, Dobson-Stone C, Rubio JP, et al. A conserved sorting-associated protein is mutant in chorea-acanthocytosis. Nat Genet. 2001; 28:119–120.

18. Ueno S, Maruki Y, Nakamura M, et al. The gene encoding a newly discovered protein, chorein, is mutated in chorea-acanthocytosis. Nat Genet. 2001; 28:121–122.

19. Dobson-Stone C, Velayos-Baeza A, Filippone LA, et al. Chorein detection for the diagnosis of chorea-acanthocytosis. Ann Neurol. 2004; 56:299–302.

20. Clark MR, Aminoff MJ, Chiu DT, et al. Red cell deformability and lipid composition in two forms of acanthocytosis: enrichment of acanthocytic populations by density gradient centrifugation. J Lab Clin Med. 1989; 113:469–481.

21. Terada N, Fujii Y, Ueda H, et al. Ultrastructural changes of erythrocyte membrane skeletons in chorea-acanthocytosis and McLeod syndrome revealed by the quick-freezing and deep-etching method. Acta Haematol. 1999; 101:25–31.

22. Olivieri O, De Franceschi L, Bordin L, et al. Increased membrane protein phosphorylation and anion transport activity in chorea-acanthocytosis. Haematologica. 1997; 82:648–653.

23. De Franceschi L, Tomelleri C, Matte A, et al. Erythrocyte membrane changes of chorea-acanthocytosis are the result of altered Lyn kinase activity. Blood. 2011; 118:5652–5663.

24. Melone MA, Di Fede G, Peluso G, et al. Abnormal accumulation of tTGase products in muscle and erythrocytes of chorea-acanthocytosis patients. J Neuropathol Exp Neurol. 2002; 61:841–848.

25▪▪. Siegl C, Hamminger P, Jank H, et al. Alterations of red cell membrane properties in nneuroacanthocytosis. PLoS ONE. 2013; 8:e76715

This is the first report on RBC response to drug-induced endovesicles from ChAc and PKAN patients.


26. Jung HH, Danek A, Frey BM. McLeod syndrome: a neurohaematological disorder. Vox Sang. 2007; 93:112–121.

27. Ho M, Chelly J, Carter N, et al. Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. Cell. 1994; 77:869–880.

28. Ho MF, Chalmers RM, Davis MB, et al. A novel point mutation in the McLeod syndrome gene in neuroacanthocytosis. Ann Neurol. 1996; 39:672–675.

29. Calenda G, Peng J, Redman CM, et al. Identification of two new members, XPLAC and XTES, of the XK family. Gene. 2006; 370:6–16.

30. Ballas SK, Bator SM, Aubuchon JP, et al. Abnormal membrane physical properties of red cells in McLeod syndrome. Transfusion. 1990; 30:722–727.

31. Redman CM, Huima T, Robbins E, et al. Effect of phosphatidylserine on the shape of McLeod red cell acanthocytes. Blood. 1989; 74:1826–1835.

32▪. De Franceschi L, Scardoni G, Tomelleri C, et al. Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. PLoS ONE. 2012; 7:e31015

This is the first computational biological analysis of the Tyr-phosphoproteome from RBC membrane of ChAc and MLS and identifies a restricted network of kinases.


33. Walker RH, Liu Q, Ichiba M, et al. Self-mutilation in chorea-acanthocytosis: manifestation of movement disorder or psychopathology? Mov Disord. 2006; 21:2268–2269.

34. Springer, Bosman GJCGM, de Franceschi L. Walker RHSS, Danek A. Neuroacanthocytosis-related changes in erythrocyte membrane organization and function. Neuroacanthocytosis syndromes II. 2008 .

35. Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med. 2003; 348:33–40.

36. Hartig MB, Hortnagel K, Garavaglia B, et al. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann Neurol. 2006; 59:248–256.

37. Zhang YM, Rock CO, Jackowski S. Biochemical properties of human pantothenate kinase 2 isoforms and mutations linked to pantothenate kinase-associated neurodegeneration. J Biol Chem. 2006; 281:107–114.

38. Zhou B, Westaway SK, Levinson B, et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet. 2001; 28:345–349.

39. Rump P, Lemmink HH, Verschuuren-Bemelmans CC, et al. A novel 3-bp deletion in the PANK2 gene of Dutch patients with pantothenate kinase-associated neurodegeneration: evidence for a founder effect. Neurogenetics. 2005; 6:201–207.

40. Murthy SN, Wilson J, Zhang Y, Lorand L. Residue Gln-30 of human erythrocyte anion transporter is a prime site for reaction with intrinsic transglutaminase. J Biol Chem. 1994; 269:22907–22911.

41. Lorand L, Graham RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol. 2003; 4:140–156.

42. Cooper AJ, Sheu KR, Burke JR, et al. Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and alpha-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length. Proc Natl Acad Sci U S A. 1997; 94:12604–12609.

43. Foller M, Hermann A, Gu S, et al. Chorein-sensitive polymerization of cortical actin and suicidal cell death in chorea-acanthocytosis. FASEB J. 2012; 26:1526–1534.

44. Pantaleo A, De Franceschi L, Ferru E, et al. Current knowledge about the functional roles of phosphorylative changes of membrane proteins in normal and diseased red cells. J Proteomics. 2010; 73:445–455.

45. Siciliano A, Turrini F, Bertoldi M, et al. Deoxygenation affects tyrosine phosphoproteome of red cell membrane from patients with sickle cell disease. Blood Cells Mol Dis. 2010; 44:233–242.

46. Brunati AM, Bordin L, Clari G, et al. Sequential phosphorylation of protein band 3 by Syk and Lyn tyrosine kinases in intact human erythrocytes: identification of primary and secondary phosphorylation sites. Blood. 2000; 96:1550–1557.

47▪▪. Slavova-Azmanova NS, Kucera N, Satiaputra J, et al. Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling. Blood. 2013; 122:262–271.

This reports the observation that mice constitutively expressing active Lyn display acanthocytes in the peripheral circulation.


48. Danek A, Walker RH. Neuroacanthocytosis. Curr Opin Neurol. 2005; 18:386–392.

49. Dobson-Stone C, Danek A, Rampoldi L, et al. Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis. Eur J Hum Genet. 2002; 10:773–781.

50. Springer, Velayos-Baeza AL, Levecque C, Dobson-Stone C, Monaco AP. Walker RH, Saiki S, Danek A. The function of chorein. Neuroacanthocytosis syndromes II. 2008; 87–105.

51. Velayos-Baeza A, Vettori A, Copley RR, et al. Analysis of the human VPS13 gene family. Genomics. 2004; 84:536–549.

52. Springer-Verlag, Velayos-Baeza A, Levecque C, Dobson-Stone C, Monaco AP. Walker RH, Saiki S, Danek A. The function of chorein. Neuro-acanthocytosis syndromes II. 2008; 87–105.

53. Stege JT, Laub MT, Loomis WF. Tip genes act in parallel pathways of early Dictyostelium development. Dev Genet. 1999; 25:64–77.

54. Abazeed ME, Blanchette JM, Fuller RS. Cell-free transport from the trans-golgi network to late endosome requires factors involved in formation and consumption of clathrin-coated vesicles. J Biol Chem. 2005; 280:4442–4450.

55. Abazeed ME, Fuller RS. Yeast Golgi-localized, gamma-Ear-containing, ADP-ribosylation factor-binding proteins are but adaptor protein-1 is not required for cell-free transport of membrane proteins from the trans-Golgi network to the prevacuolar compartment. Mol Biol Cell. 2008; 19:4826–4836.

56. Foote C, Nothwehr SF. The clathrin adaptor complex 1 directly binds to a sorting signal in Ste13p to reduce the rate of its trafficking to the late endosome of yeast. J Cell Biol. 2006; 173:615–626.

57. Tomemori Y, Ichiba M, Kusumoto A, et al. A gene-targeted mouse model for chorea-acanthocytosis. J Neurochem. 2005; 92:759–766.

58. Kurano Y, Nakamura M, Ichiba M, et al. Chorein deficiency leads to upregulation of gephyrin and GABA(A) receptor. Biochem Biophys Res Commun. 2006; 351:438–442.

59. Moriguchi S, Nishi M, Komazaki S, et al. Functional uncoupling between Ca2+ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins. Proc Natl Acad Sci U S A. 2006; 103:10811–10816.

60. Wilburn B, Rudnicki DD, Zhao J, et al. An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington's disease-like 2 mice. Neuron. 2011; 70:427–440.

61. Kuo YM, Duncan JL, Westaway SK, et al. Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum Mol Genet. 2005; 14:49–57.

62▪. Brunetti D, Dusi S, Morbin M, et al. Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model. Hum Mol Genet. 2012; 21:5294–5305.

This study further characterized pank−/− mice and identified mitochondrial dysfunction in pank2−/− neuronal cells.


63. Kuo YM, Hayflick SJ, Gitschier J. Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase-associated neurodegeneration. J Inherit Metab Dis. 2007; 30:310–317.

64. Zhang YM, Chohnan S, Virga KG, et al. Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis. Chem Biol. 2007; 14:291–302.

65. Wu Z, Li C, Lv S, Zhou B. Pantothenate kinase-associated neurodegeneration: insights from a Drosophila model. Hum Mol Genet. 2009; 18:3659–3672.

66. Bosveld F, Rana A, van der Wouden PE, et al. De novo CoA biosynthesis is required to maintain DNA integrity during development of the Drosophila nervous system. Hum Mol Genet. 2008; 17:2058–2069.

67. Russo DC, Lee S, Reid ME, Redman CM. Point mutations causing the McLeod phenotype. Transfusion. 2002; 42:287–293.

68. Khamlichi S, Bailly P, Blanchard D, et al. Purification and partial characterization of the erythrocyte Kx protein deficient in McLeod patients. Eur J Biochem. 1995; 228:931–934.

69. Russo D, Redman C, Lee S. Association of XK and Kell blood group proteins. J Biol Chem. 1998; 273:13950–13956.

70. Danek A, Rubio JP, Rampoldi L, et al. McLeod neuroacanthocytosis: genotype and phenotype. Ann Neurol. 2001; 50:755–764.

71. Walker RH, Danek A, Uttner I, et al. McLeod phenotype without the McLeod syndrome. Transfusion. 2007; 47:299–305.

72. Lee S, Russo D, Redman CM. The Kell blood group system: Kell and XK membrane proteins. Semin Hematol. 2000; 37:113–121.

73. Carbonnet F, Hattab C, Collec E, et al. Immunochemical analysis of the Kx protein from human red cells of different Kell phenotypes using antibodies raised against synthetic peptides. Br J Haematol. 1997; 96:857–863.

74. Khodadad JK, Weinstein RS, Marsh LW, Steck TL. Shape determinants of McLeod acanthocytes. J Membr Biol. 1989; 107:213–218.

75. Kuypers FA, van Linde-Sibenius Trip M, Roelofsen B, et al. The phospholipid organisation in the membranes of McLeod and Leach phenotype erythrocytes. FEBS Lett. 1985; 184:20–24.

76. Tang LL, Redman CM, Williams D, Marsh WL. Biochemical studies on McLeod phenotype erythrocytes. Vox Sang. 1981; 40:17–26.

77. Manno S, Takakuwa Y, Mohandas N. Modulation of erythrocyte membrane mechanical function by protein 4.1 phosphorylation. J Biol Chem. 2005; 280:7581–7587.

78. Salomao M, Zhang X, Yang Y, et al. Protein 4.1R-dependent multiprotein complex: new insights into the structural organization of the red blood cell membrane. Proc Natl Acad Sci U S A. 2008; 105:8026–8031.

79. Stanfield GM, Horvitz HR. The ced-8 gene controls the timing of programmed cell deaths in C. elegans. Mol Cell. 2000; 5:423–433.

80. Walker RH, Morgello S, Davidoff-Feldman B, et al. Autosomal dominant chorea-acanthocytosis with polyglutamine-containing neuronal inclusions. Neurology. 2002; 58:1031–1037.

81. Kalfa TA, Pushkaran S, Mohandas N, et al. Rac GTPases regulate the morphology and deformability of the erythrocyte cytoskeleton. Blood. 2006; 108:3637–3645.

82. Margolis R. Pagon RAAM, Bird TD, Dolan CR, et al. Huntington disease-like 2. University of Washington, Seattle, Gene reviews (TM). Seattle, WA:2004 .

83. Margolis RL, Holmes SE, Rosenblatt A, et al. Huntington's Disease-like 2 (HDL2) in North America and Japan. Ann Neurol. 2004; 56:670–674.

84. Trottier Y, Lutz Y, Stevanin G, et al. Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature. 1995; 378:403–406.

85. Johnson MA, Kuo YM, Westaway SK, et al. Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration. Ann N Y Acad Sci. 2004; 1012:282–298.

86. Poli M, Derosas M, Luscieti S, et al. Pantothenate kinase-2 (Pank2) silencing causes cell growth reduction, cell-specific ferroportin upregulation and iron deregulation. Neurobiol Dis. 2010; 39:204–210.

87. Guehl D, Cuny E, Tison F, et al. Deep brain pallidal stimulation for movement disorders in neuroacanthocytosis. Neurology. 2007; 68:160–161.

Keywords

chorea-acanthocytosis; McLeod syndrome; membrane; phosphorylation; signal transduction

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.