Elliptocytosis is a hematologic disorder characterized by elliptically shaped erythrocytes and a variable degree of hemolytic anemia. Usually inherited as an autosomal dominant, elliptocytosis results from mutation in any one of several genes encoding proteins of the red ... Elliptocytosis is a hematologic disorder characterized by elliptically shaped erythrocytes and a variable degree of hemolytic anemia. Usually inherited as an autosomal dominant, elliptocytosis results from mutation in any one of several genes encoding proteins of the red cell membrane skeleton. Elliptocytosis-1 was found in the 1950s to be linked to the Rh blood group (see 111700) and is caused by a defect in protein 4.1.
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 ... 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 Southeast 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.
Conboy et al. (1986) showed by Southern blot analysis of genomic DNA from an Algerian family that in affected members the mutant protein 4.1 gene had a DNA rearrangement upstream from the initiation codon for translation (130500.0001). The ... Conboy et al. (1986) showed by Southern blot analysis of genomic DNA from an Algerian family that in affected members 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. The failure of Bannerman and Renwick (1962) to find linkage with Rh is attributable to the fact that most of their families were black, and the defect was likely in spectrin in these families (see 182860.0003). 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.