Infantile neuroaxonal dystrophy in a pair of Malaysian siblings with progressive cerebellar atrophy: Description of an expanded phenotype with novel PLA2G6 variants.
PLA2G6-associated neurodegeneration (PLAN, NBIA2) is the second most common type of neurodegeneration with brain iron accumulation (NBIA), caused by recessive mutations of PLA2G6 gene, which encodes Ca<sup>2+</sup>-independent phospholipase A<sub>2</sub>β (iPLA<sub>2</sub>β).
Phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN) includes a series of neurodegenerative diseases that result from the mutations in <i>PLA2G6</i>.
We describe how the defective catalytic activity of the PLA2G6 gene could be potentially overcome by enzyme replacement or gene correction, giving examples and challenges specific to INAD.
Therefore, we investigate glutamate (Glu)-evoked Ca<sup>2+</sup> signals in neurons and astrocytes in co-culture obtained from three INAD mouse model strains with Pla2g6 mutations, (i) hypomorphic Pla2g6 allele with reduced transcript levels, (ii) knocked-out Pla2g6, and (iii) (G373R)-point mutation with inactive VIA iPLA<sub>2</sub> enzyme.
Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment.
Further large studies in various populations are warranted to elucidate what causes the difference in frequencies of PLA2G6 rearrangement mutations between INAD and dystonia-parkinsonism.
Thus, our findings bring new insight into molecular mechanism affected in INAD and highlight the non-canonical function of VIA iPLA2 in regulation of mitochondrial Ca(2+) handling.
The patients with INAD had PLA2G6 mutations NM_003560.2: c.[950G>T];[426-1077dup] and c.[1799G>A];[2221C>T] and the patient with dystonia-parkinsonism had PLA2G6 mutations NM_003560.2: c.[609G>A];[2222G>A].
DNA sequence analysis of the entire coding region of PLA2G6 identified 13 different mutations, including five novel ones (p.Leu224Pro, p.Asp283Asn, p.Arg329Cys, p.Leu491Phe, and p.Arg649His), in 12/22 (54.55%) families with INAD and ANAD.
Mutations in the PLA2G6 gene which encodes Ca(2+)-independent phospholipase A2 (VIA iPLA2) were detected in 85% of cases of the inherited degenerative nervous system disorder INAD (infantile neuroaxonal dystrophy, OMIM #256600).
Mutations in the PLA2G6 gene which encodes Ca(2+)-independent phospholipase A2 (VIA iPLA2) were detected in 85% of cases of the inherited degenerative nervous system disorder INAD (infantile neuroaxonal dystrophy, OMIM #256600).