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Southeast Asian ovalocytosis is a form of hereditary elliptocytosis common in some communities in Malaysia and Papua New Guinea, as it confers some resistance to cerebral Falciparum Malaria.^[1]

Pathophysiology

Southeast Asian ovalocytosis

The primary defect in SAO differs significantly from other forms of elliptocytosis in that it is a defect in the gene coding for a protein that is not directly involved in the cytoskeleton scaffolding of the cell. Rather, the defect lies in a protein known as the band 3 protein, which lies in the cell membrane itself. The band 3 protein normally binds to another membrane-bound protein called ankyrin, but in SAO this bond is stronger than normal. Other abnormalities include tighter tethering of the band 3 protein to the cell membrane, increased tyrosine phosphorylation of the band 3 protein, reduced sulfate anion transport through the cell membrane, and more rapid ATP consumption. These (and probably other) consequences of the SAO mutations lead to the following erythrocyte abnormalities:^[2]

A greater robustness of cells to a variety of external forces, including:
- Reduction in cellular sensitivity to osmotic pressures
- Reduction in fragility related to temperature change
- greater general rigidity of the cell membrane
- Loss of sensitivity to substances that cause spiculation of cells
Reduced anion exchange

Figure 3 - A representation of the steps involved in the entry of Plasmodium falciparum into an erythrocyte.
Partial intracellular depletion of ATP
A reduction in expression of multiple antigens

These changes are thought to give rise to the scientifically and clinically interesting phenomenon that those with SAO exhibit: a marked in vivo resistance to infection by the causative pathogen of malaria, Plasmodium falciparum. Unlike those with the Leach phenotype of common hereditary elliptocytosis (see above), there is a clinically significant reduction in both disease severity and prevalence of malaria in those with SAO. Because of this, the 35% incidence rate of SAO along the north coast of Madang Province in Papua New Guinea, where malaria in endemic, is a good example of natural selection.^[3]

The reasons behind the resistance to malaria become clear when given an explanation the way in which Plasmodium falciparum invades its host. This parasite is an obligate intracellular parasite, which must enter the cells of the host it is invading. The band 3 proteins aggregate on the cell membrane at the site of entry, forming a circular orifice that the parasite squeezes through. These band 3 proteins act as receptors for the parasite. Normally a process much like endocytosis occurs, and the parasite is able to isolate itself from the intracellular proteins that are toxic to it while still being inside an erythrocyte (see figure 2). The increased rigidity of the erythrocyte membrane in SAO is thought to reduce the capacity of the band 3 proteins to cluster together, thereby making it more difficult for the malaria parasite to properly attaching to and enter the cell. The reduced free ATP within the cell has been postulated as a further mechanism behind which SAO creates a hostile environment for Plasmodium falciparum.

References

^ "Prevention of cerebral malaria in children in Papua New Guinea by southeast Asian ovalocytosis band 3 -- Allen et al. 60 (6): 1056 -- American Journal of Tropical Medicine and Hygiene". Retrieved 2008-02-26.
^ Liu, S.C.; Palek, J; Nichols, PE; Derick, LH; Chiou, SS; Amato, D; Corbett, JD; Golan, DE (1 July 1995). "Molecular basis of altered red blood cell membrane properties in Southeast Asian ovalocytosis: role of the mutant band 3 protein in band 3 oligomerization and retention by the membrane skeleton". Blood 86 (1): 349. PMID 7795244.
^ Mgone, Cs; Koki, G; Paniu, Mm; Kono, J; Bhatia, Kk; Genton, B; Alexander, Nd; Alpers, Mp (May 1996). "Occurrence of the erythrocyte band 3 (AE1) gene deletion in relation to malaria endemicity in Papua New Guinea.". Transactions of the Royal Society of Tropical Medicine and Hygiene 90 (3): 228–31. doi:10.1016/S0035-9203(96)90223-0. ISSN 0035-9203. PMID 8758056.

UpToDate Contents

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1. 末梢血塗抹標本の評価 evaluation of the peripheral blood smear
2. 遺伝性楕円赤血球症：臨床的特徴、診断、および治療 hereditary elliptocytosis clinical features diagnosis and treatment
3. 遺伝性楕円赤血球症：遺伝学と病因 hereditary elliptocytosis genetics and pathogenesis
4. 赤血球表面抗原および細胞骨格蛋白質の異常によるマラリアに対する防御 protection against malaria by abnormalities in red cell surface antigens and cytoskeletal proteins
5. 貧血を有する成人患者に対するアプローチ approach to the adult patient with anemia

English Journal

Malaria and human red blood cells.

Mohandas N, An X.SourceRed Cell Physiology Laboratory, New York Blood Center, 310 East 67th Street, New York, NY, 10065, USA, MNarla@NYBloodcenter.org.
Medical microbiology and immunology.Med Microbiol Immunol.2012 Nov;201(4):593-8. doi: 10.1007/s00430-012-0272-z. Epub 2012 Sep 11.
Invasion by the malaria parasite, Plasmodium falciparum, brings about extensive changes in the host red cells. These include loss of the normal discoid shape, increased rigidity of the membrane, elevated permeability to a wide variety of ionic and other species and increased adhesiveness, most notab
PMID 22965173

Reduced Risk of Plasmodium vivax Malaria in Papua New Guinean Children with Southeast Asian Ovalocytosis in Two Cohorts and a Case-Control Study.

Rosanas-Urgell A, Lin E, Manning L, Rarau P, Laman M, Senn N, Grimberg BT, Tavul L, Stanisic DI, Robinson LJ, Aponte JJ, Dabod E, Reeder JC, Siba P, Zimmerman PA, Davis TM, King CL, Michon P, Mueller I.SourcePNG Institute of Medical Research, Madang, Papua New Guinea.
PLoS medicine.PLoS Med.2012 Sep;9(9):e1001305. Epub 2012 Sep 4.
BACKGROUND: The erythrocyte polymorphism, Southeast Asian ovalocytosis (SAO) (which results from a 27-base pair deletion in the erythrocyte band 3 gene, SLC4A1Δ27) protects against cerebral malaria caused by Plasmodium falciparum; however, it is unknown whether this polymorphism also protects again
PMID 22973182

Japanese Journal

Molecular population genetics of SLC4A1 and Southeast Asian Ovalocytosis

Wilder Jason A.,Stone Jonathan A.,Preston Elizabeth G. [他],FINN Lauren E,RATCLIFFE Hannah L,SUDOYO Herawati
Journal of human genetics 54(3), 182-187, 2009-03-01
NAID 10030729755

Ovalocytosis without band 3 gene 27-bp deletion and malaria infection

Kimura Masako,Soemantri Augustinus,Siswanto Jo Edi [他],ISHIDA TAKAFUMI
Anthropological science : journal of the Anthropological Society of Nippon 114(2), 161-164, 2006-08-01
NAID 10017650838

Austronesian origin of the 27-bp deletion of the erythrocyte band 3 gene in East Sepik, Papua New Guinea inferred from mtDNA analysis

Tsukahara Takahiro,Hombhanje Francis Wanak,Lum Jeffrey Koji [他],HWAIHWANJE Ilomo,MASTA Andrew,KANEKO Akira,KOBAYAKAWA Takatoshi
Journal of human genetics 51(3), 244-248, 2006-03-01
NAID 10018115801