Elliptocytosis 1

A number sign (#) is used with this entry because of evidence that elliptocytosis-1 (EL1) is caused by heterozygous or homozygous mutation in the gene encoding erythrocyte membrane protein 4.1 (EPB41; 130500) on chromosome 1p35.

Description

Elliptocytosis is a hematologic disorder characterized by elliptically shaped erythrocytes and a variable degree of hemolytic anemia. Usually inherited as an autosomal dominant trait, elliptocytosis results from mutation in any one of several genes encoding proteins of the red cell membrane skeleton (summary by McGuire et al., 1988).

Genetic Heterogeneity of Elliptocytosis

Elliptocytosis-2 (130600) is caused by mutation in the SPTA1 gene (182860). Elliptocytosis-3 (617948) is caused by mutation in the SPTB gene (182870). Elliptocytosis-4 (166900), also known as Southeast Asian ovalocytosis, is caused by mutation in the SLC4A1 gene (109270). Also see pyropoikilocytosis (266140).

See Delaunay (2007) for a discussion of the molecular basis of hereditary red cell membrane disorders.

Clinical Features

Because of the existence of at least 2 forms of elliptocytosis, one linked to Rh and one unlinked (Morton, 1956), phenotypic differences correlating with the differences in linkage relationships were sought. Geerdink et al. (1967) found more hemolysis in the 'unlinked' type than in the 'linked' type. Lux and Wolfe (1980) delineated 6 clinical varieties of hereditary elliptocytosis (HE). Peters et al. (1966), studying isolated red cell membranes, demonstrated an abnormality in erythrocyte sodium transport. The extensive study of elliptocytosis in Iceland reported by Jensson et al. (1967) showed how widely the manifestations may vary. All cases were plausibly considered to have the same gene. Additional evidence of heterogeneity in elliptocytosis may be provided by the effects of combination with beta-thalassemia. Aksoy and Erdem (1968) concluded that the combination sometimes results in mutual enhancement, whereas in other instances it does not.

Nielsen and Strunk (1968) described a Dutch family in which, among the 7 offspring of related parents, both with elliptocytosis, 2 died in infancy of severe anemia; a third had erythrocytes that showed more marked morphologic changes than in heterozygotes and had severe anemia which was compensated by splenectomy. All 3 were presumably homozygotes. Three other sibs were heterozygotes and one was stillborn. The elliptocytosis was of the Rh-linked variety. Lipton (1955) had reported an instance of presumed homozygosity; both parents had elliptocytosis without hemolysis and were second cousins. The child had hemolytic anemia. Splenectomy was beneficial.

Early demonstrations of abnormalities of band 4.1 were provided by Alloisio et al. (1981) and Tchernia et al. (1981). Tchernia et al. (1981) studied a family in which 3 of 5 sisters had severe hemolytic anemia, marked red cell fragmentation, and elliptocytic poikilocytosis. They were presumed to be homozygotes because both parents and a clinically unaffected (or minimally affected) sister had conventional elliptocytosis and were probably heterozygous. The parents were consanguineous. All 7 members of the nuclear family were Rh-identical (Rh-negative), making linkage study impossible. Band 4.1 in the red cell membrane proteins was markedly reduced in the 3 patients and reduced to an intermediate level in the 3 putative heterozygotes. Thus, band 4.1 is probably central to normal membrane stability and normal cell shape. The critical role of protein 4.1 in red cell membrane stability was demonstrated by the restoration of normal membrane stability with purified protein 4.1 (Takakuwa et al., 1986).

Alloisio et al. (1982) described a heritable variant of protein 4.1 that consists of shortening by about 75 amino acids, affecting both subcomponents a and b and involving one or more phosphorylation sites. The proposita was normal and was identified because of complete lack of protein 4.1 in her son with elliptocytosis. The father had elliptocytosis and reduced band 4.1. The son was presumably a compound heterozygote. Homozygotes with elliptocytosis and total absence of band 4.1 were described also by Feo et al. (1980). Morle et al. (1985) gave further information on the family reported by Alloisio et al. (1982) and referred to the variant as protein 4.1 Presles.

Alloisio et al. (1985) suggested that the heterozygous state of this form of hereditary elliptocytosis, called the 4.1(-) trait, results in a characteristic clinical picture. In the course of an elliptocytosis screening of 10 families from southeastern France and North Africa, Alloisio et al. (1985) found 4 in which a clinically silent, dominantly transmitted form of hereditary elliptocytosis was associated in every case with a decrease of band 4.1. In the other families, band 4.1 was normal, clinical signs were sometimes present, and in 3 the mode of inheritance was uncertain. Whereas heterozygous 4.1 deficiency accounts for one-fourth to one-third of hereditary elliptocytosis in Caucasians, homozygosity is rare. Dalla Venezia et al. (1992) suggested that the rarity of homozygous 4.1 deficiency is related to the severe effects on other cell types in addition to red cells.

Dhermy et al. (1986) reported studies of 38 cases of hereditary elliptocytosis. Fifteen patients showed a deficiency in protein 4.1. The other 24 patients showed a spectrin self-association defect (type I HE). A shortened spectrin beta chain was found in 1 family with a spectrin self-association defect. All patients with the protein 4.1 deficiency were Caucasian; most of the type I HE cases were of black extraction.

Lambert and Zail (1987) described partial deficiency of protein 4.1 as the cause of autosomal dominant hereditary elliptocytosis. They studied a total of 14 families, of which 1 was black, residing in South Africa.

Morle et al. (1987) described 2 sibs with severe congenital hemolytic anemia and red cells displaying a variety of abnormal shapes. Protein 4.1 was reduced by 30%. The parents, who were consanguineous, were devoid of any biochemical abnormality; however, their red cells were not normal. Whether the primary defect resided in protein 4.1 was not clear.

Mapping

On the basis of a family segregating for elliptocytosis and PGD (172200) as well as the common polymorphisms Rh, PGM1 and alpha-fucosidase, Cook et al. (1977) concluded that the map of 1p is, in the male, 1pter--PGD--18%--El--2%--Rh--2%--alpha-FUC--25%--PGM1--centromere. In the female, the above intervals were estimated to be 22, 4, 2, and 37%, respectively.

As knowledge of the molecular genetics of the red cell membrane proteins advanced, light was thrown on the early demonstration of linkage of Rh with one form of elliptocytosis and nonlinkage with other forms. The protein 4.1 gene was mapped to chromosome 1pter-p32 (Conboy et al. (1985, 1986)) by hybridization to chromosomes sorted onto nitrocellulose filters using a fluorescence-activated cell sorter. Studies of translocations also localized the gene to chromosome 1pter-p32, the region of the Rh gene (Kan, 1986). Thus, it seemed certain that the protein 4.1 gene is mutant in Rh-linked elliptocytosis. Parra et al. (1998) stated that the EPB41 gene is located on chromosome 1p33-p32.

Molecular Genetics

By Southern blot analysis of genomic DNA from affected members of an Algerian family with elliptocysis, Conboy et al. (1986) showed that the mutant protein 4.1 gene had a DNA rearrangement upstream from the initiation codon for translation (130500.0001). The mRNA from the mutant gene was aberrantly spliced.

McGuire and Agre (1987) demonstrated Rh linkage in 2 Caucasian families with a defect in protein 4.1. In 1 family the 4.1 band showed a reduction to about 65% of normal; in the other, a high molecular weight 4.1 was present. (A third proband had unstable 4.1.)

McGuire et al. (1988) found that variants of erythrocyte protein 4.1 were inherited in linkage with elliptocytosis and with Rh type in 3 white families.

Partial deletion of protein 4.1 was found in 1 family with elliptocytosis (Kan, 1986).

Lambert et al. (1988) found an elliptocytosis family in which an apparent rearrangement of the coding region of the protein 4.1 gene led to restriction fragment length polymorphism when DNA was tested using a fragment of the cDNA that encompassed the coding region of the gene.

History

In a family in which both elliptocytosis and hereditary hemorrhagic telangiectasia were segregating, Roberts (1945) pointed out that even small bodies of data are useful for excluding close linkage. The elliptocytosis/Rh linkage was one of the first autosomal linkages to be demonstrated (Morton, 1956).