exudates and Acidosis--Renal-Tubular

Mutations of the AE1 (SLC4A1, Anion-Exchanger 1) gene that codes for band 3, the renal and red cell anion exchanger, are responsible for many cases of familial distal renal tubular acidosis (dRTA). In Southeast Asia this disease is usually recessive, caused either by homozygosity of a single AE1 mutation or by compound heterozygosity of two different AE1 mutations. We describe two unrelated boys in Sarawak with dRTA associated with compound heterozygosity of AE1 mutations. Both had Southeast Asian ovalocytosis (SAO), a morphological abnormality of red cells caused by a deletion of band 3 residues 400-408. In addition, one boy had a DNA sequence abnormality of band 3 residue (G701D), which has been reported from elsewhere in Southeast Asia. The other boy had the novel sequence abnormality of band 3 (Q759H) and profound hemolytic anemia.

Topics: Acidosis, Renal Tubular; Anion Exchange Protein 1, Erythrocyte; Diseases in Twins; Female; Genes, Recessive; Humans; Infant, Newborn; Malaysia; Male; Mutation; Pedigree

We have previously demonstrated that compound heterozygous (SAO/G701D) and homozygous (G701D/G701D) mutations of the anion exchanger 1 (AE1) gene, encoding erythroid and kidney AE1 proteins, cause autosomal recessive distal renal tubular acidosis (AR dRTA) in Thai patients. It is thus of interest to examine the prevalence of these mutations in the Thai population. The SAO and G701D mutations were examined in 844 individuals from north, northeast, central, and south Thailand. Other reported mutations including R602H, DeltaV850, and A858D were also examined in some groups of subjects. The SAO mutation was common in the southern Thai population; its heterozygote frequency was 7/206 and estimated allele frequency 1.70%. However, this mutation was not observed in populations of three other regions of Thailand. In contrast, the G701D mutation was not found in the southern population but was observed in the northern, northeastern, and central populations, with heterozygote frequencies of 1/216, 3/205, and 1/217, and estimated allele frequencies of 0.23%, 0.73%, and 0.23%, respectively. The higher allele frequency of the G701D mutation in the northeastern Thai population corresponds to our previous finding that all Thai patients with AR dRTA attributable to homozygous G701D mutation originate from this population. This suggests that the G701D allele that is observed in this region might arise in northeastern Thailand. The presence of patients with compound heterozygous SAO/G701D in southern Thailand and Malaysia and their apparently absence in northeastern Thailand indicate that the G701D allele may have migrated to the southern peninsular region where SAO is common, resulting in pathogenic allelic interaction.

Topics: Acidosis, Renal Tubular; Anion Exchange Protein 1, Erythrocyte; DNA Mutational Analysis; DNA Primers; Gene Frequency; Genes, Recessive; Genetic Carrier Screening; Genetic Testing; Homozygote; Humans; Malaysia; Mutation; Polymerase Chain Reaction; Thailand

Southeast Asian ovalocytosis (SAO) is a red blood cell abnormality common in malaria-endemic regions and caused by a 27 nt deletion of the band 3 protein gene. Since band 3 protein, also known as anion exchanger 1, is expressed in renal distal tubules, the incidence of SAO was examined in distal renal tubular acidosis (dRTA) in Malays in Kelantan, Malaysia. Twenty-two patients with dRTA and 50 healthy volunteers were examined for complication of SAO by both morphological and genetic analyses. SAO was identified in 18 of the 22 dRTA patients (81.8%), but only two of the 50 controls (4%). The incidence of SAO was significantly high in those with dRTA (p<0.001), indicating a dysfunctional role for band 3 protein/anion exchanger 1 in the development of dRTA.

Topics: Acidosis, Renal Tubular; Adult; Anion Exchange Protein 1, Erythrocyte; Child; Child, Preschool; Elliptocytosis, Hereditary; Erythrocytes; Female; Gene Deletion; Humans; Infant; Malaysia; Male; Middle Aged

We describe three mutations of the red-cell anion exchangerband 3 (AE1, SLC4A1) gene associated with distalrenal tubular acidosis (dRTA) in families from Malaysia and Papua NewGuinea: Gly(701)-->Asp (G701D), Ala(858)-->Asp(A858D) and deletion of Val(850) (DeltaV850). The mutationsA858D and DeltaV850 are novel; all three mutations seem to berestricted to South-East Asian populations. South-East Asianovalocytosis (SAO), resulting from the band 3 deletion of residues400-408, occurred in many of the families but did not itselfresult in dRTA. Compound heterozygotes of each of the dRTA mutationswith SAO all had dRTA, evidence of haemolytic anaemia and abnormal red-cell properties. The A858D mutation showed dominant inheritance and therecessive DeltaV850 and G701D mutations showed a pseudo-dominantphenotype when the transport-inactive SAO allele was also present. Red-cell and Xenopus oocyte expression studies showed that theDeltaV850 and A858D mutant proteins have greatly decreased aniontransport when present as compound heterozygotes (DeltaV850/A858D,DeltaV850/SAO or A858D/SAO). Red cells with A858D/SAO had only 3% ofthe SO(4)(2-) efflux of normal cells, thelowest anion transport activity so far reported for human red cells. The results suggest dRTA might arise by a different mechanism for eachmutation. We confirm that the G701D mutant protein has an absoluterequirement for glycophorin A for movement to the cell surface. Wesuggest that the dominant A858D mutant protein is possibly mis-targetedto an inappropriate plasma membrane domain in the renal tubular cell,and that the recessive DeltaV850 mutation might give dRTA because ofits decreased anion transport activity.

Topics: Acidosis, Renal Tubular; Adolescent; Adult; Anion Exchange Protein 1, Erythrocyte; Child; Child, Preschool; Chlorides; Elliptocytosis, Hereditary; Erythrocytes; Female; Humans; Ion Transport; Malaysia; Male; Mutation; New Guinea; Pedigree

Renal tubular acidosis (RTA) is a defect in urinary acidification in the absence of renal failure. All records of patients admitted to adult medical wards at the University Hospital USM (HUSM), Kelantan between 1986 to 1990 with the diagnosis of renal tubular acidosis were reviewed. Sixteen (16) patients were identified and fulfilled the diagnostic criteria. Their mean age at presentation was 28.9 +/- 0.74 years. The triad of muscle weakness, hypokalaemia and systemic metabolic acidosis were the characteristic features at presentation. Normal serum alkaline phosphatase and skeletal X-rays were noted. Their prognosis were generally good. Their mean serum bicarbonate and potassium on follow up were 17.84 +/- 0.35 and 3.82 +/- 0.05 mmol/L respectively. The importance of regular follow-up and long-term management is emphasised.

Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Adult; Bicarbonates; Female; Humans; Hydrogen-Ion Concentration; Incidence; Malaysia; Retrospective Studies