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Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities

Nature Genetics volume 23, pages 264–266 (1999)Cite this article

Proximal renal tubular acidosis (pRTA) results from an impairment of bicarbonate (HCO3–) reabsorption in the renal proximal tubules, characterized by a decreased renal HCO3– threshold1. pRTA commonly occurs as a manifestation of a generalized functional defect in proximal tubules (Fanconi syndrome), but it is an isolated phenomenon that is mostly transient1. In contrast, permanent isolated pRTA is rare and usually occurs with ocular abnormalities2,3,4,5. More than 85% of the filtered load of HCO3– is reabsorbed in the renal proximal tubules. This transepithelial flux is accomplished by an apical membrane Na+/H+ exchanger and a basolateral Na+/HCO3– co-transporter6 (NBC; encoded by SLC4A4).

So far, salamander, rat and human kidney and pancreatic SLC4A4 cDNAs have been identified7,8,9,10,11. We detected two inactivating homozygous mutations in kidney SLC4A4 in two unrelated patients having permanent isolated pRTA with ocular abnormalities.

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Figure 1: Mutations in kidney SLC4A4 cDNA and genomic DNA in two patients.
Figure 2: Functional expression of wild-type NBC and R298S and R510H mutants.

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Acknowledgements

We thank the patients and their families for participation. Support for this study was provided by the Ministry of Education, Science, Sport and Culture of Japan (grant 11670741) and the Ministry of Health and Welfare of Japan.

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Authors and Affiliations

  1. Department of Pediatrics, Faculty of Medicine, The University of Tokyo, Mejirodai Campus, Tokyo, Japan

    Takashi Igarashi

  2. Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan

    Jun Inatomi, Takashi Sekine, Seok Ho Cha, Yoshikatsu Kanai & Hitoshi Endou

  3. Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Motoei Kunimi, Kazuhisa Tsukamoto, Hiroaki Satoh & George Seki

  4. Department of Genetics, Mitsubishi Kagaku Bio-Chemical Labo, Inc., Tokyo, Japan

    Mitsunobu Shimadzu & Fumiko Tozawa

  5. Department of Pediatrics, School of Medicine, Shinshu University, Nagano, Japan

    Tetsuo Mori & Masaaki Shiobara

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  1. Takashi Igarashi
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Correspondence to Takashi Igarashi.

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Igarashi, T., Inatomi, J., Sekine, T. et al. Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities. Nat Genet 23, 264–266 (1999). https://doi.org/10.1038/15440

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