A novel mutation has been identified in CA4 that provides further evidence that impaired pH regulation may underlie photoreceptor degeneration in RP17. This study indicates that, as with European patients with RP, mutations in CA4 also account for

Anion exchanger 1 (AE1, 6 band 3, SLC4A1) is a bicarbonate transporter involved in maintaining acid-base homeostasis in the human body (1). There are two human forms of AE1, erythroid (eAE1) and kidney (kAE1). eAE1 or band 3, is the major integral membrane glycoprotein of the erythrocyte, where it serves dual roles of Cl Ϫ /HCO 3 Ϫ exchange and cytoskeletal anchorage to red cell membranes (2). kAE1 is the basolateral Cl Ϫ /HCO 3 Ϫ exchanger of the acid-secreting ␣-intercalated cell of the kidney distal tubule (3). Transcription of eAE1 in erythroid precursors is under the control of an erythroid-specific promoter upstream of exon 1, whereas renal transcription arises from a distinct promoter within intron 3 of the AE1 gene (4). Thus, the resultant kidney transcript encodes the kAE1 polypeptide lacking 65 amino acids present at the N terminus of human eAE1 (5). This structural alteration causes major functional differences between eAE1 and kAE1. The N terminus of eAE1 interacts with many proteins, including ankyrin, proteins 4.1, and glycolytic enzymes (3, 6), whereas the N terminus of kAE1 does not bind to these proteins (7,8).The three-dimensional structure of the N-terminal 43-kDa cytoplasmic domain of eAE1 revealed a globular structure, composed of 11 ␤-strands and 10 ␣-helical segments arranged as an N-terminal interaction domain and a C-terminal dimerization domain (2), but no structure is available for kAE1. Residues 58 -68 of eAE1 form the first ␤-strand in the cytoplasmic domain. Loss of a central strand of ␤-sheet in kAE1 may thus greatly alter the globular structure of the cytosolic domain, thereby altering its protein interactions. Furthermore, the identity of kAE1-binding protein(s) in ␣-intercalated cells remains unknown. Previously a protein called kanadaptin (kidney anion exchanger adaptor protein) was reported to interact with mouse N-terminal kAE1 but not to eAE1 (9). Human kanadaptin does not, however, interact with human kAE1 and localizes predominantly to the nucleus (10). This leads to the question: * This work was supported in part by Canadian Institutes of Health Research operating grants (to J. R. C. and R. A. F. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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