The X-linked human gene ATP6AP2 (ATPase H+ transporting accessory protein 2) has been implicated in several neurological diseases (see FBhh0000787); recently, specific variants of ATP6AP2 have been implicated in a subtype of congenital disorder of glycosylation (CDG2R). ATP6AP2 encodes a transmembrane protein that is an essential accessory component of a vacuolar ATPase thought to be required for lysosomal degradative functions and autophagy. There is a single orthologous gene in Drosophila, ATP6AP2, for which a loss-of-function mutation, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
A UAS construct with a tagged wild-type human Hsap\ATP6AP2 has been introduced into flies; partial heterologous rescue (functional complementation) of the Dmel\ATP6AP2 amorphic phenotypes has been observed.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): L98S in the fly ATP6AP2 gene (corresponds to L98S in the human ATP6AP2 gene). Flies carrying a transgenic copy of the L98S mutation in an ATP6AP2 null background typically die during the pupal stage; the surviving adults display poor mobility and reduced lifespan; larvae exhibit brain developmental defects and impaired lipid homeostasis.
Animals homozygous for an amorphic allele of Dmel\AATP6AP2 die in the larval stage; in somatic clones, planar cell polarity defects are observed. Neuronal loss of function of ATP6AP2 effected by RNAi results in locomotor, memory, and neuroanatomy defects. Physical and genetic interactions have been described for Dmel\ATP6AP2; see below and in the ATP6AP2 gene report.
[updated Mar. 2021 by FlyBase; FBrf0222196]
[CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIr; CDG2R](https://omim.org/entry/301045)
[ATPase, H+ TRANSPORTING, LYSOSOMAL, ACCESSORY PROTEIN 2; ATP6AP2](https://omim.org/entry/300556)
The predominant symptoms of the three identified males are hepatopathy and immunodeficiency. Additional clinical features observed are cutis laxa, and in some patients, dysmorphic features, mild intellectual disability, and mild ataxia. (FBrf0237364)
Congenital disorder of glycosylation type 2R (CDG2R) is an X-linked recessive disorder characterized by infantile onset of liver failure, recurrent infections due to hypogammaglobulinemia, and cutis laxa. Some patients may also have mild intellectual impairment and dysmorphic features (summary by Rujano et al., 2017; pubmed:29127204.) [from MIM:301045; 2021.03.21]
Two hemizygous mutations in ATP6AP2 were identified by whole exome sequencing in three male individuals from two unrelated families included in cohorts of unsolved CDG cases (FBrf0237364).
Congenital disorder of glycosylation type 2R (CDG2R) is caused by hemizygous mutation in the ATP6AP2 gene
[from MIM:301045; 2021.03.21]
The ATP6AP2 gene encodes a transmembrane protein that is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy (summary by Korvatska et al., 2013; pubmed:23595882). [from MIM:300556; 2018.04.12]
One to one (1 human to 1 Drosophila).
Moderate- to high-scoring ortholog of human ATP6AP2 (1 Drosophila to 1 human). Dmel\ATP6AP2 shares 26% identity and 47% similarity with the human gene.
