Journal Article

Distinct classes of trafficking rBAT mutants cause the type I cystinuria phenotype

Paola Bartoccioni, Mònica Rius, Antonio Zorzano, Manuel Palacín and Josep Chillarón

in Human Molecular Genetics

Volume 17, issue 12, pages 1845-1854
Published in print June 2008 | ISSN: 0964-6906
Published online March 2008 | e-ISSN: 1460-2083 | DOI:
Distinct classes of trafficking rBAT mutants cause the type I cystinuria phenotype

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Most mutations in the rBAT subunit of the heterodimeric cystine transporter rBAT-b0,+AT cause type I cystinuria. Trafficking of the transporter requires the intracellular assembly of the two subunits. Without its partner, rBAT, but not b0,+AT, is rapidly degraded. We analyzed the initial biogenesis of wild-type rBAT and type I cystinuria rBAT mutants. rBAT was degraded, at least in part, via the ERAD pathway. Assembly with b0,+AT within the endoplasmic reticulum (ER) blocked rBAT degradation and could be independent of the calnexin chaperone system. This system was, however, necessary for post-assembly maturation of the heterodimer. Without b0,+AT, wild-type and rBAT mutants were degraded with similar kinetics. In its presence, rBAT mutants showed strongly reduced (L89P) or no transport activity, failed to acquire complex N-glycosylation and to oligomerize, suggesting assembly and/or folding defects. Most of the transmembrane domain mutant L89P did not heterodimerize with b0,+AT and was degraded. However, the few [L89P]rBAT-b0,+AT heterodimers were stable, consistent with assembly, but not folding, defects. Mutants of the rBAT extracellular domain (T216M, R365W, M467K and M467T) efficiently assembled with b0,+AT but were subsequently degraded. Together with earlier results, the data suggest a two-step biogenesis model, with the early assembly of the subunits followed by folding of the rBAT extracellular domain. Defects on either of these steps lead to the type I cystinuria phenotype.

Journal Article.  6596 words.  Illustrated.

Subjects: Genetics and Genomics

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