This report describes Fabry disease, an X-linked disease described as a lysosomal storage disease. The human gene implicated in this disease is GLA, which encodes alpha-galactosidase. Severe disease is found in males deficient in GLA; heterozygous females and males with residual GLA activity typically develop disease phenotypes later in life. The Drosophila gene orthologous to GLA, CG7997, has not been used in this disease model.
Multiple UAS constructs of the human Hsap\GLA gene have been introduced into flies, including wild-type and variants implicated in disease. Variant(s) implicated in human disease tested (as transgenic human gene, GLA): the A156V and A285D variant forms of the human gene have been introduced into flies.
This fly system has been used to test and confirm the hypothesis that dysfunctional GLA variants are recognized as misfolded in the ER and undergo ER-associated degradation. Expression of the pathological variants in dopaminergic neurons results cell death of the affected neurons, locomotor defects, and reduced lifespan; the A285D variant exhibits more severe phenotypes. In the case of the A156V variant, but not the A285D variant, these phenotypes are ameliorated upon treatment with migalastat, a standard therapy for Fabry disease.
[updated Nov. 2020 by FlyBase; FBrf0222196]
[FABRY DISEASE](https://omim.org/entry/301500)
[GALACTOSIDASE, ALPHA; GLA](https://omim.org/entry/300644)
Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. The disorder is a systemic disease, manifest as progressive renal failure, cardiac disease, cerebrovascular disease, small-fiber peripheral neuropathy, and skin lesions, among other abnormalities (Schiffmann, 2009; pubmed:19318041). An atypical variant of Fabry disease has been reported in which cardiac disease, specifically left ventricular hypertrophy, with or without renal failure, develops in the sixth decade of life. These patients have residual GLA activity (Nakao et al., 1995, pubmed:7596372; Nakao et al., 2003, pubmed:12911529). Although Fabry disease was previously considered to be an X-linked recessive disorder, Wang et al. (2007; pubmed:17224688) found that heterozygous women with Fabry disease experience significant life-threatening conditions requiring medical treatment and intervention. Thus, heterozygous Fabry women should not be called carriers, as this term underestimates the seriousness of the disease in these patients. [from MIM:301500; 2020.11.05]
Fabry disease is caused by mutations in the GLA gene, encoding alpha-galactosidase A, on chromosome X. Heterozygous females and males with residual GLA activity typically develop disease phenotypes later in life. [from MIM:301500; 2020.11.05]
GLA encodes alpha-galactosidase A, a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [Gene Cards, GLA; 2020.11.05]
Many to one: 2 human genes to 1 Drosophila gene.
