The homozygous state for the band 3 protein mutation in Southeast Asian Ovalocytosis may be lethal [letter]

Liu, Shih‐Chun; Jarolim, P; Rubin, Hillard; Palek, J; Amato, Dominick; Hassan, Khalid; Zaik, Mahmood; Sapak, Peter

doi:10.1182/blood.v84.10.3590.bloodjournal84103590

Cited by 36 publications

(21 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This interaction may stabilize the folding of AE1 SAO enough to escape retention by quality control in the ER, thus allowing AE1 SAO to traffic to the cell surface. Therefore, in the hypothetical case of homozygous SAO, which may be embryonic lethal [13], mature erythrocytes may contain inactive AE1 SAO at the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Trafficking defects of the Southeast Asian ovalocytosis deletion mutant of anion exchanger 1 membrane proteins

Cheung

Cordat

Reithmeier

2005

Biochemical Journal

View full text Add to dashboard Cite

Human AE1 (anion exchanger 1) is a membrane glycoprotein found in erythrocytes and as a truncated form (kAE1) in the BLM (basolateral membrane) of a-intercalated cells of the distal nephron, where they carry out electroneutral chloride/bicarbonate exchange. SAO (Southeast Asian ovalocytosis) is a dominant inherited haematological condition arising from deletion of Ala400-Ala408 in AE1, resulting in a misfolded and transport-inactive protein present in the ovalocyte membrane. Heterozygotes with SAO are able to acidify their urine, without symptoms of dRTA (distal renal tubular acidosis) that can be associated with mutations in kAE1. We examined the effect of the SAO deletion on stability and trafficking of AE1 and kAE1 in transfected HEK-293 (human embryonic kidney) cells and kAE1 in MDCK (Madin-Darby canine kidney) epithelial cells. In HEK-293 cells, expression levels and stabilities of SAO proteins were significantly reduced, and no mutant protein was detected at the cell surface. The intracellular retention of AE1 SAO in transfected HEK-293 cells suggests that erythroid-specific factors lacking in HEK-293 cells may be required for cell-surface expression. Although misfolded, SAO proteins could form heterodimers with the normal proteins, as well as homodimers. In MDCK cells, kAE1 was localized to the cell surface or the BLM after polarization, while kAE1 SAO was retained intracellularly. When kAE1 SAO was co-expressed with kAE1 in MDCK cells, kAE1 SAO was largely retained intracellularly; however, it also co-localized with kAE1 at the cell surface. We propose that, in the kidney of heterozygous SAO patients, dimers of kAE1 and heterodimers of kAE1 SAO and kAE1 traffic to the BLM of a-intercalated cells, while homodimers of kAE1 SAO are retained in the endoplasmic reticulum and are rapidly degraded. This results in sufficient cell-surface expression of kAE1 to maintain adequate bicarbonate reabsorption and proton secretion without dRTA.

show abstract

Section: Discussionmentioning

confidence: 99%

“…more rigid than normal [11], individuals with SAO are generally asymptomatic, with no anaemia or dRTA [12]. However, the homozygous state of SAO may be embryonic lethal [13]. SAO erythrocytes contain approximately equal amounts of AE1 and AE1 SAO [14].…”

Section: Figure 1 Folding Model Of Human Ae1mentioning

confidence: 99%

Trafficking defects of the Southeast Asian ovalocytosis deletion mutant of anion exchanger 1 membrane proteins

Cheung

Cordat

Reithmeier

2005

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…Although SAO AE1 can form heterodimers with normal AE1 [92], it does not fold into a transport-competent conformation [93,94]. Individuals with SAO are uniformly heterozygous for the trait; homozygosity is lethal in utero [95]. When expressed in HEK-293 and MDCK cells, SAO AE1 was retained in the ER but when co-expressed with the normal AE1, SAO AE1 was partially targeted to the plasma membrane in both non-polarized and polarized MDCK cells [96].…”

Section: Southeast Asian Ovalocytosismentioning

confidence: 99%

Bicarbonate transport in cell physiology and disease

Cordat

Casey

2008

Biochemical Journal

151

184

View full text Add to dashboard Cite

The family of mammalian bicarbonate transport proteins are involved in a wide-range of physiological processes. The importance of bicarbonate transport follows from the biochemistry of HCO(3)(-) itself. Bicarbonate is the waste product of mitochondrial respiration. HCO(3)(-) undergoes pH-dependent conversion into CO(2) and in doing so converts from a membrane impermeant anion into a gas that can diffuse across membranes. The CO(2)-HCO(3)(-) equilibrium forms the most important pH buffering system of our bodies. Bicarbonate transport proteins facilitate the movement of membrane-impermeant HCO(3)(-) across membranes to accelerate disposal of waste CO(2), control cellular and whole-body pH, and to regulate fluid movement and acid/base secretion. Defects of bicarbonate transport proteins manifest in diseases of most organ systems. Fourteen gene products facilitate mammalian bicarbonate transport, whose physiology and pathophysiology is discussed in the present review.

show abstract

“…The trait is caused by a 27 base-pair deletion in SLC4A1, the gene encoding the erythrocyte membrane Band 3 protein (Jarolim et al, 1991). SAO is associated with heterozygous carriers of the deletion, and when homozygous the mutation is fully lethal in utero in the absence of extraordinary medical intervention (Genton et al, 1995;Liu et al, 1994;Picard et al, 2014). Evidence for a heterozygote advantage for individuals with SAO in malarial areas comes from case-control studies that have demonstrated nearly complete protection conferred by SAO against severe clinical malaria (including cerebral malaria) and malaria-related mortality caused by Plasmodium falciparum (Allen et al, 1999;Genton et al, 1995;Rosanas-Urgell et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The evolutionary origins of Southeast Asian Ovalocytosis

Paquette

Harahap

Laosombat

et al. 2015

Infection, Genetics and Evolution

View full text Add to dashboard Cite

Southeast Asian Ovalocytosis (SAO) is a common red blood cell disorder that is maintained as a balanced polymorphism in human populations. In individuals heterozygous for the SAO-causing mutation there are minimal detrimental effects and well-documented protection from severe malaria caused by Plasmodium vivax and Plasmodium falciparum; however, the SAO-causing mutation is fully lethal in utero when homozygous. The present-day high frequency of SAO in Island Southeast Asia indicates the trait is maintained by strong heterozygote advantage. Our study elucidates the evolutionary origin of SAO by characterizing DNA sequence variation in a 9.5 kilobase region surrounding the causal mutation in the SLC4A1 gene. We find substantial haplotype diversity among SAO chromosomes and estimate the age of the trait to be approximately 10,005 years (95% CI: 4930-23,200 years). This date is far older than any other human malaria-resistance trait examined previously in Southeast Asia, and considerably pre-dates the widespread adoption of agriculture associated with the spread of speakers of Austronesian languages some 4000 years ago. Using a genealogy-based method we find no evidence of historical positive selection acting on SAO (s=0.0, 95% CI: 0.0-0.03), in sharp contrast to the strong present-day selection coefficient (e.g., 0.09) estimated from the frequency of this recessively lethal trait. This discrepancy may be due to a recent increase in malaria-driven selection pressure following the spread of agriculture, with SAO targeted as a standing variant by positive selection in malarial populations.

show abstract

The homozygous state for the band 3 protein mutation in Southeast Asian Ovalocytosis may be lethal [letter]

Cited by 36 publications

References 0 publications

Trafficking defects of the Southeast Asian ovalocytosis deletion mutant of anion exchanger 1 membrane proteins

Trafficking defects of the Southeast Asian ovalocytosis deletion mutant of anion exchanger 1 membrane proteins

Bicarbonate transport in cell physiology and disease

The evolutionary origins of Southeast Asian Ovalocytosis

Contact Info

Product

Resources

About