The reference OMIM entry for this protein is 300913

Vma21, s. cerevisiae, homolog of; vma21

DESCRIPTION

VMA21 is the human homolog of yeast Vma21, an essential assembly chaperone of the vacuolar ATPase (V-ATPase; see 607027) (Ramachandran et al., 2013).

CLONING

Ramachandran et al. (2013) reported that human VMA21 shares less than 22% amino acid similarity with yeast Vma21 and lacks a critical dilysine endoplasmic reticulum (ER) return signal. They found that VMA21 was expressed ubiquitously as a 4.7-kb transcript. In human fibroblasts and mouse C2C12 myoblasts, VMA21 localized to the ER, to COPII (see 610511) vesicles, and to the ER-Golgi intermediate compartment, similar to yeast Vma21. However, unlike yeast Vma21, mammalian VMA21 was not present in the Golgi and did not cycle back to the ER.

GENE FUNCTION

The S. cerevisiae V-ATPase is a multisubunit complex composed of a peripheral membrane (V1) sector and an integral membrane (V0) sector. Malkus et al. (2004) showed that yeast Vma21 has an essential role in coordinating assembly of V0 subunits and in escorting the assembled V0 complex into ER-derived transport vesicles. Ramachandran et al. (2013) showed that human VMA21 fully rescued a yeast strain lacking Vma21. They found that immunoprecipitation of VMA21 in light membrane fractions of HEK293 cells coprecipitated the V0 complex, similar to findings in yeast. Immunocytochemical analysis showed colocalization of VMA21 with V-ATPase subunits. Immunoprecipitation analysis suggested that VMA21 interacts with the V0 complex, at least in part, through the c-prime-prime subunit (ATP6V0B; 603717). An earlier study on VMA21 by Ramachandran et al. (2009) was retracted by the authors in 2010 due to errors in data presentation, but not due to the validity of the conclusions.

GENE STRUCTURE

Ramachandran et al. (2013) determined that the VMA21 gene has 3 exons.

MAPPING

Ramachandran et al. (2013) stated that the VMA21 gene maps to chromosome Xq28.

MOLECULAR GENETICS

In 45 patients with X-linked myopathy with excessive autophagy (XMEA; 310440) from 14 families, Ramachandran et al. (2013) identified 6 different single-nucleotide substitutions in the VMA21 gene. Four of these were intronic; 1 occurred in coding sequence but abolished a predicted splice enhancer site; and 1 occurred after the termination codon in the 3-prime UTR. Ramachandran et al. (2013) found that cells from patients with XMEA had elevated lysosomal pH and a resultant partial block in the common final degradative stage of autophagy. Quantitative RT-PCR from patient fibroblasts and lymphoblasts revealed 32 to 58% reduction in VMA21 mRNA, including in patients with the 3-prime UTR mutation. Western blot analysis and immunohistochemistry showed that VMA21 protein was also reduced, and V-ATPase activity was reduced to 10 to 30% of normal values. Transfection experiments with mutant and wildtype minigenes showed greater than 40% decrease in mRNA from the variant minigenes compared to wildtype. Patient cells also showed a compensatory increase in macroautophagy, partially through inhibition of the mTOR pathway (601231) via reduced levels of cellular free amino acids. Restoration of VMA21 levels in cells with silenced VMA21 restored the normal morphology. The patients were previously reported in a paper retracted from Cell in 2009 (Ramachandran et al., 2009). In a 52-year-old Japanese man with XMEA, Kurashige et al. (2013) identified a hemizygous intronic mutation in the VMA21 gene (300913.0004). In 2 brothers wit ... More on the omim web site

Subscribe to this protein entry history

Oct. 20, 2018: Protein entry updated
Automatic update: OMIM entry 300913 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).