ClinVar Genomic variation as it relates to human health

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 (166900), Jarolim et al. (1991) demonstrated that the EPB3 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. 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 (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. Mohandas et al. (1992) likewise demonstrated the deletion of amino acids 400-408 in the boundary between the cytoplasmic and the first transmembrane domains of band 3. The biophysical consequences of the mutation was a marked decrease in lateral mobility of band 3 and an increase in membrane rigidity. Mohandas et al. (1992) suggested that the mutation induces a conformational change in the cytoplasmic domain of band 3, leading to its entanglement in the skeletal protein network. This entanglement inhibits the normal unwinding and stretching of the spectrin tetramers necessary for membrane extension, leading to increased rigidity. The same deletion of 9 amino acids was found by Tanner et al. (1991) in a Mauritian Indian and by Ravindranath et al. (1994) in an African American mother and daughter. All cases of SAO had been associated with the Memphis-1 polymorphism (109270.0001), which is found in all populations but is present at higher frequency in American Indian and African American populations. However, SAO had not previously been identified in African Americans. The band 3 deletion in Southeast Asian ovalocytosis may prevent cerebral malaria (611162), but it exacerbates malarial anemia and may also increase acidosis, a major determinant of mortality in malaria. Allen et al. (1999) undertook a case-control study of children admitted to hospital in a malarious area of Papua New Guinea. The 24-bp deletion, detected by PCR, was present in 0 of 68 children with cerebral malaria, compared with 6 (8.8%) of 68 matched community controls. Median hemoglobin levels were 1.2 g/dl lower in malaria cases with Southeast Asian ovalocytosis than in controls (P = 0.035), but acidosis was not affected. The band 3 protein mediates the cytoadherence of parasitized erythrocytes in vitro. The remarkable protection that the SAO variant affords against cerebral malaria may offer a valuable approach to a better understanding of the mechanisms of adherence of parasitized erythrocytes to vascular endothelium and the pathogenesis of cerebral malaria. The abnormal SAO protein does not mediate chloride transport (Groves et al., 1993), and homozygosity for the 9-amino acid deletion is apparently lethal (Liu et al., 1994). Yusoff et al. (2003) examined the incidence of SAO in Malays in Kelantan, Malaysia, who had distal renal tubular acidosis. SAO was identified in 18 of the 22 distal renal tubular acidosis patients (81.8%), but in only 2 of the 50 controls (4%). Yusoff et al. (2003) referred to the band 3 variant as a 27-nt deletion. In a population-based study of 19 individuals each from Japan, Taiwan, and Indonesia, Wilder et al. (2009) found the 27-bp deletion associated with the SAO trait in 4 of the Indonesian samples only. These 4 SAO chromosomes also carried the Memphis variant (109270.0001). The haplotype associated with the 27-bp deletion was also found in Japanese samples, but not in Taiwanese samples, which was a surprising finding since Taiwan was thought to be part of the Austronesian population expansion. The findings indicated that chromosomes related to Indonesian SAO alleles are not a major component of genetic diversity among aboriginal Taiwanese, and suggested that the SLC4A1 gene is subject to natural selection. (less)

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 (166900), Jarolim et al. (1991) demonstrated that the EPB3 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. 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 (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. Mohandas et al. (1992) likewise demonstrated the deletion of amino acids 400-408 in the boundary between the cytoplasmic and the first transmembrane domains of band 3. The biophysical consequences of the mutation was a marked decrease in lateral mobility of band 3 and an increase in membrane rigidity. Mohandas et al. (1992) suggested that the mutation induces a conformational change in the cytoplasmic domain of band 3, leading to its entanglement in the skeletal protein network. This entanglement inhibits the normal unwinding and stretching of the spectrin tetramers necessary for membrane extension, leading to increased rigidity. The same deletion of 9 amino acids was found by Tanner et al. (1991) in a Mauritian Indian and by Ravindranath et al. (1994) in an African American mother and daughter. All cases of SAO had been associated with the Memphis-1 polymorphism (109270.0001), which is found in all populations but is present at higher frequency in American Indian and African American populations. However, SAO had not previously been identified in African Americans. The band 3 deletion in Southeast Asian ovalocytosis may prevent cerebral malaria (611162), but it exacerbates malarial anemia and may also increase acidosis, a major determinant of mortality in malaria. Allen et al. (1999) undertook a case-control study of children admitted to hospital in a malarious area of Papua New Guinea. The 24-bp deletion, detected by PCR, was present in 0 of 68 children with cerebral malaria, compared with 6 (8.8%) of 68 matched community controls. Median hemoglobin levels were 1.2 g/dl lower in malaria cases with Southeast Asian ovalocytosis than in controls (P = 0.035), but acidosis was not affected. The band 3 protein mediates the cytoadherence of parasitized erythrocytes in vitro. The remarkable protection that the SAO variant affords against cerebral malaria may offer a valuable approach to a better understanding of the mechanisms of adherence of parasitized erythrocytes to vascular endothelium and the pathogenesis of cerebral malaria. The abnormal SAO protein does not mediate chloride transport (Groves et al., 1993), and homozygosity for the 9-amino acid deletion is apparently lethal (Liu et al., 1994). Yusoff et al. (2003) examined the incidence of SAO in Malays in Kelantan, Malaysia, who had distal renal tubular acidosis. SAO was identified in 18 of the 22 distal renal tubular acidosis patients (81.8%), but in only 2 of the 50 controls (4%). Yusoff et al. (2003) referred to the band 3 variant as a 27-nt deletion. In a population-based study of 19 individuals each from Japan, Taiwan, and Indonesia, Wilder et al. (2009) found the 27-bp deletion associated with the SAO trait in 4 of the Indonesian samples only. These 4 SAO chromosomes also carried the Memphis variant (109270.0001). The haplotype associated with the 27-bp deletion was also found in Japanese samples, but not in Taiwanese samples, which was a surprising finding since Taiwan was thought to be part of the Austronesian population expansion. The findings indicated that chromosomes related to Indonesian SAO alleles are not a major component of genetic diversity among aboriginal Taiwanese, and suggested that the SLC4A1 gene is subject to natural selection. (less)