The vacuolar-ATPase B1 subunit in distal tubular acidosis: novel mutations and mechanisms for dysfunction

Fuster, Daniel Guido; Zhang, J; Xie, X-S; Moe, O W (2008). The vacuolar-ATPase B1 subunit in distal tubular acidosis: novel mutations and mechanisms for dysfunction. Kidney international, 73(10), pp. 1151-8. New York, N.Y.: Nature Publishing Group 10.1038/ki.2008.96

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Mutations in the B1 subunit of the multisubunit vacuolar ATPase cause autosomal-recessive distal renal tubular acidosis and sensorineural deafness. Here, we report a novel frameshift mutation that truncates the C-terminus of the human B1 subunit. This mutant protein failed to assemble with other subunits in the cytosol to form the complex that can be targeted to vesicular structures in mammalian cells. Loss of proton pump activity was demonstrated in a functional complementation assay in B-subunit null yeast. The mutation caused loss of a discreet C-terminal region critical for subunit interaction not related to the C-terminal PDZ motif. Co-expression studies failed to demonstrate dominant negative effects of this truncated mutant over wild-type B1. Analysis of 12 reported B1 subunit missense mutations showed one polymorphic allele had intact pump function, two point mutants had intact assembly but defective proton pumping, and the remaining nine had disrupted assembly with no pump function. One presumed polymorphic allele was actually an inactivating mutation. Our study shows that multiple mechanisms of pump dysfunction result from B1 subunit mutations with a common outcome being defective assembly. Polymorphisms of the B1 subunit in the general population may affect renal acidification and urinary chemistry.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension

UniBE Contributor:

Fuster, Daniel Guido

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0085-2538

ISBN:

18368028

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:05

Last Modified:

28 Jan 2016 11:07

Publisher DOI:

10.1038/ki.2008.96

PubMed ID:

18368028

Web of Science ID:

000255411600009

BORIS DOI:

10.7892/boris.28099

URI:

https://boris.unibe.ch/id/eprint/28099 (FactScience: 116688)

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