CNS glycosylphosphatidylinositol deficiency results in delayed white matter development, ataxia and premature death in a novel mouse model.

Abstract

The glycosylphosphatidylinositol (GPI) anchor is a post-translational modification added to approximately 150 different proteins to facilitate proper membrane anchoring and trafficking to lipid rafts. Biosynthesis and remodeling of the GPI anchor requires the activity of over 20 distinct genes. Defects in the biosynthesis of GPI anchors in humans lead to inherited glycosylphosphatidylinositol deficiency (IGD). IGD patients display a wide range of phenotypes though the central nervous system (CNS) appears to be the most commonly affected tissue. A full understanding of the etiology of these phenotypes has been hampered by the lack of animal models due to embryonic lethality of GPI biosynthesis gene null mutants. Here we model IGD by genetically ablating GPI production in the CNS with a conditional mouse allele of phosphatidylinositol glycan anchor biosynthesis, class A (Piga) and Nestin-Cre. We find that the mutants do not have structural brain defects but do not survive past weaning. The mutants show progressive decline with severe ataxia consistent with defects in cerebellar development. We show that the mutants have reduced myelination and defective Purkinje cell development. Surprisingly, we found that Piga was expressed in a fairly restricted pattern in the early postnatal brain consistent with the defects we observed in our model. Thus, we have generated a novel mouse model of the neurological defects of IGD which demonstrates a critical role for GPI biosynthesis in cerebellar and white matter development.

• Authors: Marshall Lukacs, Lauren E Blizzard, Rolf W Stottmann
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 29 Issue 7 Pg. 1205-1217 (05 08 2020) ISSN: 1460-2083 [Electronic] England
• PMID: 32179897 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Glycosylphosphatidylinositols

Topics

• Animals
• Central Nervous System (metabolism, pathology)
• Central Nervous System Diseases (genetics, pathology)
• Cerebellar Ataxia (genetics, metabolism, pathology)
• Disease Models, Animal
• Glycosylphosphatidylinositols (deficiency, genetics)
• Humans
• Mice
• Mortality, Premature
• Mutation (genetics)
• Phenotype
• Seizures (genetics, pathology)
• White Matter (metabolism, pathology)