Familial pure proximal renal tubular acidosis--a clinical and genetic study.
BACKGROUND
Inherited proximal renal tubular acidosis (pRTA) is commonly associated with more generalized proximal tubular dysfunctions and occasionally with other organ system defects. Inherited combined pRTA and distal RTA with osteopetrosis and pure pRTA associated with ocular abnormalities, a rare disease which has been recently described. Only one family with pure isolated pRTA has been reported so far and the genetic cause for this disease is unknown. Objectives. We report a unique family with isolated pRTA. The aim of the project was to define the phenotype and to try to find the gene defect causing the disease.


METHODS
Clinical and metabolic evaluation of all family members was performed and a family pedigree was constructed. DNA was extracted from blood samples of affected and unaffected family members. We amplified by PCR and sequenced the coding areas and splice-sites of the genes that contribute to HCO(-)(3) reclamation in the proximal tubule. The genes studied were as follows: CA II, CA IV, CA XIV, NCB1, Na(+)/H(+) exchanger (NHE)-3, NHE-8, the regulatory proteins of NHE3, NHRF1 and NHRF2 and the Cl(-)/HCO(-)(3) exchanger, SLC26A6.


RESULTS
The father and all four children had RTA with blood HCO(-)(3) levels of 11-14 meq/l and urine pH of 5.3-5.4. Increased HCO(-)(3) fractional excretion after bicarbonate loading to 40-60% confirmed the diagnosis pRTA. No other tubular dysfunction was found, and no organ system dysfunction was detected, besides short stature. No mutation was found in all candidate genes studied.


CONCLUSIONS
We presented a second family in the literature with familial isolated pure pRTA. The mode of inheritance is compatible with an autosomal dominant disease. Because of the small size of the family, wide genome search was not applicable and the gene candidate approach was chosen. Nine important candidate genes were extensively studied but the molecular basis of the disease was not yet found and genotyping nine important gene candidates were negative.
Katzir
Ze'ev
Z
Ze'ev Katzir, Pediatric Nephrology Services, E. Wolfson Medical Center, Holon, Israel. katzir@wolfson.health.gov.il
Dinour
Dganit
D
Reznik-Wolf
Haike
H
Nissenkorn
Andrea
A
Holtzman
Eliezer
E
D000136:Acid-Base Equilibrium; D000141:Acidosis, Renal Tubular / Q000235:genetics* / Q000378:metabolism; D027321:Anion Transport Proteins / Q000097:blood / Q000235:genetics; D001639:Bicarbonates / Q000097:blood / Q000652:urine; D015415:Biomarkers / Q000097:blood* / Q000652:urine; D024402:Carbonic Anhydrase II / Q000097:blood / Q000235:genetics; D030741:Carbonic Anhydrase IV / Q000097:blood / Q000235:genetics; D002256:Carbonic Anhydrases / Q000097:blood / Q000235:genetics; D004247:DNA / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000097:blood / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D027982:Sodium-Bicarbonate Symporters / Q000097:blood / Q000235:genetics; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000097:blood / Q000235:genetics; D000076988:Sulfate Transporters
D027321:Anion Transport Proteins; D001639:Bicarbonates; D015415:Biomarkers; D005819:Genetic Markers; D026901:Membrane Transport Proteins; C473560:SLC26A1 protein, human; C439529:SLC26A6 protein, human; C498898:SLC4A4 protein, human; C081517:SLC9A2 protein, human; C000613385:SLC9A3 protein, human; C486775:SLC9A8 protein, human; D027982:Sodium-Bicarbonate Symporters; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; D004247:DNA; D024402:Carbonic Anhydrase II; D030741:Carbonic Anhydrase IV; D002256:Carbonic Anhydrases; C466621:carbonic anhydrase XIV