PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron

Abstract

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.

Figure 1

Schematic showing iPLA₂-VIA protein structure and mutation-derived changes. Variant 1 is shown with seven ankyrin repeats (blue), a proline-rich motif (purple box), a glycine-rich nucleotide binding motif (green diamond), a lipase motif (red with the active site, Ser519, highlighted), a proposed C-terminal Ca²⁺-dependent calmodulin binding domain (purple) and three putative caspase cleavage sites (blue arrows). Numbers indicate amino acids. Substitutions or deletions of amino acids not altering the reading frame are shown above the diagram; nonsense mutations, splice mutations and deletions causing frameshifts are shown below. A deletion encompassing exons 14 through 17, the 3′of PLA2G6 and exons 1 and 2 of a downstream putative transcript, FLJ22582, is shown at the C terminus.