PLA2G6 mutations found in neurodegenerative disorders featuring high levels of brain iron

Morgan NV et al. (2006) PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nature Genet 38: 752–754

A high level of iron in the brain is a feature associated with Parkinson's disease and Alzheimer's disease. High levels of brain iron also occur in patients with neurodegeneration with brain iron accumulation (NBIA) and in some patients with infantile neuroaxonal dystrophy (INAD). Researchers have recently investigated the molecular bases of these two neuroaxonal dystrophies, using genome-wide linkage studies in 12 families with INAD and a large consanguineous family with NBIA.

A locus for both INAD and NBIA was mapped to chromosome 22q12–q13. Mutations in the PLA2G6 gene (which encodes phospholipase A₂, an enzyme that is critical in cell membrane homeostasis) were detected in both patients with INAD and those with NBIA, but were not present in matched controls. In total, 44 unique mutations were found, 32 of which were missense mutations; 85% of the missense mutations occurred at amino acid positions that are conserved in vertebrates. Brain MRI changes showing high levels of iron have not often been reported in INAD, but 40% of kindreds with mutation-positive INAD showed high brain iron in this study.

The authors conclude that defective phospholipid metabolism is implicated in neurodegenerative diseases featuring brain iron dyshomeostasis. This link between phospholipid defects and brain iron metabolism might lead to novel neuroprotective therapies.