Ovalocytosis, Southeast Asian

A number sign (#) is used with this entry because Southeast Asian ovalocytosis (SAO) is caused by a heterozygous 27-bp deletion in the SLC4A1 gene (109270) on chromosome 17q21.

Description

Southeast Asian ovalocytosis is a hereditary red blood cell disorder that is widespread in certain ethnic groups of Malaysia, Papua New Guinea, the Philippines, and Indonesia. Ovalocytic erythrocytes are rigid and exhibit reduced expression of many erythrocyte antigens. The ovalocytes are resistant to invasion in vitro by several strains of malaria, including Plasmodium falciparum and Plasmodium knowlesi (summary by Jarolim et al., 1991). The disorder is most often asymptomatic but has been reported to be associated with signs of mild hemolysis such as intermittent jaundice and gallstones (summary by Reardon et al., 1993).

Clinical Features

Lie-Injo (1965) first pointed out the high frequency of ovalocytosis in studies of Malaysian Orang Asli. Lie-Injo et al. (1972), Ganesan et al. (1975), and Baer et al. (1976) extended the observations in Malaysia, where frequencies as high as 39% were found. Ganesan et al. (1975) reported an extraordinarily high frequency of ovalocytosis among the Land Dayaks (12.7%) and Sea Dayaks (9.0%), the indigenous people of Sarawak.

Amato and Booth (1977), Booth et al. (1977), and Holt et al. (1981) identified another focus of high frequency of elliptocytosis in Melanesia (Papua New Guinea, Sarawak). The morphologic change in the red cells was apparently responsible for a previously described depression of blood group antigens (Booth, 1972), e.g., Gerbich blood group (616089), which was thought to be recessively inherited. Red cells in this condition are ovalocytes, which are often macrocytic; some, called stomatocytes, have a longitudinal slit in the middle. Indeed, stomatocytic hereditary elliptocytosis, or stomatocytic HE, is a synonym.

Kidson et al. (1981) found that ovalocytic erythrocytes from Melanesians are resistant to invasion by malaria parasites, thus providing a plausible explanation for the polymorphism (also see Serjeantson et al., 1977). This may be a mutation of a structural protein of the red cell that endows the bearer with a selective advantage.

Hadley et al. (1983) showed that Melanesian elliptocytes are highly resistant to invasion by Plasmodium knowlesi and P. falciparum in vitro. This is the only human red cell variant known to be resistant to both.

Baer (1988) suggested that Malaysian elliptocytosis may be a balanced polymorphism, i.e., that individuals homozygous for the elliptocytosis allele, not clearly identifiable by any assay, may be differentially susceptible to mortality, whereas the heterozygote is at an advantage.

Liu et al. (1990) found a structurally and functionally abnormal band 3 protein in Southeast Asian ovalocytosis. The abnormal protein binds tightly to ankyrin, thus leading to increased rigidity of the red cells, and in some way is responsible for the resistance of the red cells to invasion by malaria parasites.

Jones et al. (1990) concluded that the markedly increased phosphorylation of band 3 protein in whole red cells or isolated ghosts from ovalocytic individuals might be explained by the following findings. The cytoplasmic domain of the ovalocyte band 3 was found to be approximately 3 kD larger than the normocytic protein. The N-terminal sequence of the ovalocytic band 3 was different from the reported sequence, suggesting that the increased size resulted from an N-terminal extension. This is the region of band 3 that is phosphorylated and interacts with the red cell cytoskeleton.

Inheritance

Fix et al. (1982) reported the findings in studies of Malaysian Orang Asli families and concluded that inheritance is autosomal dominant. They quoted Kidson et al. (1981) as stating that 'in 3 of 4 families involving the marriage of a Melanesian ovalocytic and a Caucasian normocytic person, we have found ovalocytic children.'

Mapping

Liu et al. (1990) performed linkage studies in 14 families with SAO and obtained a lod score of 7.0 for linkage between the molecular defect in the band 3 protein and ovalocytosis. One of the patients they studied was Filipino.

Molecular Genetics

Following up on the demonstration by Liu et al. (1990) that a structurally and functionally abnormal band 3 protein shows absolute linkage with the SAO phenotype, Jarolim et al. (1991) demonstrated that the EPB3 (SLC4A1) gene in these cases contains a 27-bp deletion, resulting in deletion of 9 amino acids (codons 400-408) in the boundary of cytoplasmic and membrane domains of the band 3 protein (109270.0002). The defect was detected in all 30 ovalocytic subjects from Malaysia, the Philippines, and 2 unrelated coastal regions of Papua New Guinea, whereas it was absent in all 30 controls from Southeast Asia and 20 subjects of different ethnic origin from the United States. The lys56-to-glu mutation (K56E; 109270.0001) was also found in all SAO subjects; however, it was detected in 5 of 50 control subjects as well, suggesting that it represents a linked polymorphism.

Liu et al. (1994) suggested that the homozygous state for the BND3 27-bp deletion in Southeast Asian ovalocytosis may be lethal. In a group of 6 families in which both parents were heterozygous for the SAO 27-bp deletion and the K56E band 3-Memphis mutation, there were 35 offspring; 12 of these were available for testing and 10 were found to be heterozygous for both mutations, whereas the other 2 did not carry either. Specifically, none was homozygous for the SAO 27-bp deletion. The authors suggested that there was an increased frequency of miscarriages in these families.

Coetzer et al. (1996) described a 4-generation South African kindred with dominantly inherited ovalocytosis and hemolytic anemia. All affected subjects exhibited varying degrees of hemolytic anemia. Additionally, there was evidence for independent segregation of the band 3 Memphis I polymorphism (109270.0001) and the SAO 27-bp deletion in BND3. Six SAO subjects and all 3 normal family members were heterozygous for the band 3 Memphis I polymorphism and one SAO subject was homozygous for this mutation.

History

Cutting et al. (1965) reported 7 affected members in 3 generations of a Caucasian family with 3 instances of male-to-male transmission. All 7 had 'full ovalocytes' and 6 had uncompensated hemolytic anemia which underwent remission with splenectomy.

Kjellman et al. (1980) described a family with hemolytic ovalocytosis; each of 2 brothers sustained splenic rupture after relatively minor trauma.