Tissue-Specific Amino Acid Transporter Partners ACE2 and Collectrin Differentially Interact With Hartnup Mutations

Simone M.R. Camargo, Dustin Singer, Victoria Makrides, Katja Huggel, Klaas M. Pos, Carsten A. Wagner, Keiji Kuba, Ursula Danilczyk, Flemming Skovby, Robert Kleta, Josef M. Penninger, François Verrey

Research output: Contribution to journalArticlepeer-review

221 Citations (Scopus)


Background & Aims: Hartnup amino acid transporter B0AT1 (SLC6A19) is the major luminal sodium-dependent neutral amino acid transporter of small intestine and kidney proximal tubule. The expression of B0AT1 in kidney was recently shown to depend on its association with collectrin (Tmem27), a protein homologous to the membrane-anchoring domain of angiotensin-converting enzyme (ACE) 2. Methods: Because collectrin is almost absent from small intestine, we tested the hypothesis that it is ACE2 that interacts with B0AT1 in enterocytes. Furthermore, because B0AT1 expression depends on an associated protein, we tested the hypothesis that Hartnup-causing B0AT1 mutations differentially impact on B0AT1 interaction with intestinal and kidney accessory proteins. Results: Immunofluorescence, coimmunoprecipitation, and functional experiments using wild-type and ace2-null mice showed that expression of B0AT1 in small intestine critically depends on ACE2. Coexpressing new and previously identified Hartnup disorder-causing missense mutations of B0AT1 with either collectrin or ACE2 in Xenopus laevis oocytes showed that the high-frequency D173N and the newly identified P265L mutant B0AT1 transporters can still be activated by ACE2 but not collectrin coexpression. In contrast, the human A69T and R240Q B0AT1 mutants cannot be activated by either of the associated proteins, although they function as wild-type B0AT1 when expressed alone. Conclusions: We thus show that ACE2 is necessary for the expression of the Hartnup transporter in intestine and suggest that the differential functional association of mutant B0AT1 transporters with ACE2 and collectrin in intestine and kidney, respectively, participates in the phenotypic heterogeneity of human Hartnup disorder.

Original languageEnglish
Pages (from-to)872-882.e3
Issue number3
Publication statusPublished - Mar 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology


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