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Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss
  1. E H Stover1,
  2. K J Borthwick1,
  3. C Bavalia1,
  4. N Eady1,
  5. D M Fritz1,
  6. N Rungroj1,
  7. A B S Giersch3,
  8. C C Morton3,
  9. P R Axon4,
  10. I Akil5,
  11. E A Al-Sabban6,
  12. D M Baguley4,
  13. S Bianca7,
  14. A Bakkaloglu8,
  15. Z Bircan9,
  16. D Chauveau10,
  17. M-J Clermont11,
  18. A Guala12,
  19. S A Hulton13,
  20. H Kroes14,
  21. G Li Volti7,
  22. S Mir5,
  23. H Mocan15,
  24. A Nayir16,
  25. S Ozen8,
  26. J Rodriguez Soriano17,
  27. S A Sanjad18,
  28. V Tasic19,
  29. C M Taylor13,
  30. R Topaloglu8,
  31. A N Smith1,
  32. F E Karet1,2
  1. 1Department of Medical Genetics, University of Cambridge, UK
  2. 2Department of Nephrology, University of Cambridge, UK
  3. 3Departments of Pathology and Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
  4. 4Department of Otolaryngology, University of Cambridge, UK
  5. 5Izmir University, Turkey
  6. 6Department of Paediatrics, King Faisal Hospital, Riyadh, Saudi Arabia
  7. 7Department of Paediatrics, University of Catania, Italy
  8. 8Department of Paediatric Nephrology and Endocrinology, Hacettepe University, Ankara, Turkey
  9. 9Department of Paediatric Nephrology, Kocaeli University, Istanbul, Turkey
  10. 10Department of Nephrology, Hopital Necker, Paris, France
  11. 11Department of Paediatrics, Hopital Sainte-Justine, Montreal, Quebec
  12. 12Department of Paediatrics, Hospital SS Pietro e Paolo, Borgosesia, Italy
  13. 13Department of Nephrology, Birmingham Children’s Hospital, UK
  14. 14Department of Medical Genetics, University of Groningen, The Netherlands
  15. 15Department of Paediatrics, Metropolitan Florence Nightingale Hospital, Istanbul, Turkey
  16. 16Istanbul University Medical School, Istanbul, Turkey
  17. 17Department of Paediatrics, Hospital Infantil de Cruces, Baracaldo, Spain
  18. 18American University, Beirut, Lebanon
  19. 19Department of Paediatric Nephrology, Children’s Clinic, Skopje, Macedonia
  1. Correspondence to:
 Dr F E Karet, Departments of Medical Genetics and Nephrology, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Box 139, Cambridge CB2 2XY, UK;


Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal α-intercalated cell’s apical H+-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively.

We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity.

In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in “sporadic” cases.

The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.

  • renal tubular acidosis
  • H+-ATPase
  • kidney
  • hearing loss
  • rdRTA, autosomal recessive distal renal tubular acidosis
  • SNP, single nucleotide polymorphism
  • SNHL, sensorineural hearing loss
  • WT, wild type
  • DHPLC, denaturing high performance liquid chromatography
  • RT, reverse transcription
  • SSCP, single strand conformation polymorphism

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