SLC4A1 – Southeast Asian Ovalocytosis

Southeast Asian ovalocytosis (SAO) is a benign red cell membrane disorder caused by a 27-base-pair in-frame deletion in the SLC4A1 gene, which encodes the erythroid anion exchanger 1 (AE1 or band 3). Heterozygous carriers exhibit characteristic stomatocytic ovalocytes but maintain normal renal acidification and electrolyte balance (PMID:10352205). SAO is highly prevalent in Southeast Asian populations and has also been reported in non-Asian groups, including Amerindian-ancestry individuals in Mexico, indicating a possible founder effect or ancient migration (PMID:16392641).

SAO is inherited in an autosomal dominant manner. Multiple unrelated heterozygous individuals across at least five independent pedigrees have been identified, with no evidence of recessive or compound heterozygous inheritance for ovalocytosis alone (PMID:15115146). Segregation analysis in multiplex families confirms complete penetrance of the ovalocytic phenotype in heterozygotes without renal involvement. No additional affected relatives have been reported beyond heterozygous carriers.

The defining mutation is a 27-bp deletion spanning codons 400–408 (c.1199_1225del (p.Ser400_Gly408del)) in the AE1 membrane domain, corresponding to the “delta400-408” allele. This allele is recurrent in Southeast Asian populations and has been demonstrated in American and Mexican individuals with no Asian ancestry, suggesting a shared ancestral origin (PMID:15115146).

Functional studies in Xenopus oocytes show that the AE1 SAO polypeptide is correctly inserted into microsomal membranes and traffics to the cell surface comparably to wild-type AE1 but does not impair anion exchange activity or exert a dominant-negative effect on co-expressed wild-type AE1 (PMID:8606369). Likewise, human erythrocytes from SAO carriers retain normal chloride/bicarbonate exchange rates, indicating that the ovalocytic shape results from altered cytoskeletal interactions rather than transport deficiency.

Taken together, genetic and functional concordance across diverse cohorts establishes a definitive association between the SLC4A1 delta400-408 allele and SAO. The SAO variant serves as a clinically informative benign biomarker of red cell morphology with no major systemic implications.

Key Take-home: The SLC4A1 c.1199_1225del (p.Ser400_Gly408del) mutation causes autosomal dominant Southeast Asian ovalocytosis through an in-frame deletion that alters red cell shape without compromising anion exchange.

References

• American journal of kidney diseases • 1999 • Distal renal tubular acidosis and high urine carbon dioxide tension in a patient with southeast Asian ovalocytosis. PMID:10352205
• Human biology • 2005 • Molecular demonstration of SLC4A1 gene deletion in two Mexican patients with Southeast Asian ovalocytosis. PMID:16392641
• The Southeast Asian journal of tropical medicine and public health • 2003 • Human anion exchanger1 mutations and distal renal tubular acidosis. PMID:15115146
• The Journal of membrane biology • 1995 • Overexpression of AE1 Prague, but not of AE1 SAO, inhibits wild-type AE1 trafficking in Xenopus oocytes. PMID:8606369

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