In human, there are several PIGA-related disorders (see MIM:311770), two of which include seizure phenotypes; all exhibit sex-linked recessive inheritance. The gene implicated in these disorders, PIGA, is one of several proteins required for the first step of GPI anchor biosynthesis. There is a single orthologous gene in Drosophila, Dmel\PIG-A, for which a number of genetic reagents have been generated, including RNAi-targeting constructs, and CRISPR-mediated knockout and overexpression genotypes.
The human Hsap\PIGA gene has been introduced into flies, but has not been characterized.
Animals homozygous for an amorphic PIG-A mutation typically die during the larval stage. Heterozygous null adults appear wild type, but when challenged using a bang-sensitive assay they exhibit a seizure phenotype analogous to that observed in human for the PIGA-related disorders multiple congenital anomalies-hypotonia-seizures syndrome 2 (MIM:300868) and neurodevelopmental disorder with epilepsy and hemochromatosis (MIM:301072). Cell-type-specific phenotypes are observed: neuron-specific knockdown of PIG-A, mediated by RNAi, results in reduced lifespan and a number of neurological phenotypes but no seizure phenotype; glia-specific knockdown reduces lifespan and results in a very strong seizure phenotype.
A mutation analogous to a human variant implicated in PIGA-related disease has been introduced into the fly gene; see the 'Disease-Implicated Variants' table below.
[updated May 2025 by FlyBase; FBrf0222196]
[MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 2; MCAHS2](https://omim.org/entry/300868)
[PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS A PROTEIN; PIGA](https://omim.org/entry/311770)
OMIM groups 4 diseases that affect GPI anchor biosynthesis in the phenotypic series 'Multiple congenital anomalies-hypotonia-seizures syndrome' (MCAHS; MIM:PS614080).
Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) is described as a neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012; pubmed:22305531). The phenotype shows clinical variability with regard to severity and extraneurologic features. [from MIM:300868; 2024.07.30]
The PIGA gene is an X-linked in human; associated disorders exhibit recessive inheritance. [from MIM:311770; 2024.07.30]
Glycosylphosphatidylinositol (GPI) is a glycolipid that attaches dozens of different proteins to the cell surface. PIGA is 1 of several proteins required for the first step of GPI anchor biosynthesis (review by Brodsky, 2008; pubmed:18063459). [from MIM:311770; 2024.07.30]
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human PIGA (1 Drosophila gene to 1 human).
