Deficient acidification results in a novel metabolic disease

Timal, Sharita.png

Deficient acidification results in a novel metabolic disease with abnormal protein glycosylation

An international research team, including investigators of the Radboud UMC and Radboud University, has uncovered the mechanism of a novel inherited disease. The research, led by Dirk Lefeber and carried out by Eric Jansen and Sharita Timal (photo), researchers from the research institutes Donders and RIMLS, was reported in the recent issue of  Nature Communications. 

Cellular acidification is important for many biological processes, including secretion and processing of proteins. The V-ATPase is the main regulator of intra-organellar acidification. Assembly of this complex has extensively been studied in yeast, while limited knowledge is available about the mechanisms of this process in man. A group of male patients was identified with hemizygous missense mutations in X-linked ATP6AP1, encoding Ac45, the accessory protein of the V-ATPase complex. Patients displayed an immunodeficiency phenotype with frequent infections and poor response to childhood vaccinations, which was associated with hypogammaglobulinemia. In addition, this novel disease was characterized by hepatopathy and a spectrum of neurocognitive abnormalities, and can easily be identified via abnormal protein glycosylation in patient plasma.

Research on Ac45 has upto now been carried out in mammalian endocrine and neuronal cells, in the absence of a known yeast ortholog. Using an approach of homology detection at the level of sequence profiles, Martijn Huynen at the CMBI indicated Ac45 as the long-sought human homologue of yeast V-ATPase assembly factor Voa1. Subsequent experiments confirmed that wild-type Ac45, but not its disease mutants, can restore V-ATPase-dependent growth in Voa1 mutant yeast. Further research by Eric Jansen and Sharita Timal revealed that in human, Ac45 is processed in a tissue-specific way. In human brain, Ac45 is present as the expected ∼40 kDa form, in liver as the 62-kDa intact protein, and in B-cells as a novel 50-kDa unglycosylated variant. Pulse-chase experiments in liver cells revealed that liver Ac45 contains high-mannose type glycosylation, which is in agreement with localization to the ER. Glycomics analysis of total plasma N-glycans and of specific proteins revealed that Ac45 has a different effect on the glycosylation of individual proteins, indicating that Ac45 influences secretion and processing of proteins in a protein-specific way. 

In summary, the work unmasks Ac45 as the functional ortholog of yeast V-ATPase assembly factor Voa1 and reveals a novel link of tissue-specific V-ATPase assembly with immunoglobulin production and cognitive function.

Eric Jansen, Sharita Timal, Margret Ryan et al, Nature Communications 2016 May 27.

ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation.

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