Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA).

OBJECTIVE: Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult-onset parkinsonism-dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA. METHODS: Using autozygosity mapping and candidate gene sequencing, we identified mutations in the fatty acid hydroxylase gene FA2H, newly implicating abnormalities of ceramide metabolism in the pathogenesis of NBIA. RESULTS: Neuroimaging demonstrated T2 hypointensity in the globus pallidus, confluent T2 white matter hyperintensities, and profound pontocerebellar atrophy in affected members of two families. Phenotypically, affected family members exhibited spastic quadriparesis, ataxia, and dystonia with onset in childhood and episodic neurological decline. Analogous to what has been reported previously for PLA2G6, the phenotypic spectrum of FA2H mutations is diverse based on our findings and those of prior investigators, because FA2H mutations have been identified in both a form of hereditary spastic paraplegia (SPG35) and a progressive familial leukodystrophy. INTERPRETATION: These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA.

Discordant expression of miR-103/7 and pantothenate kinase host genes in mouse.

miR-103 and miR-107, microRNAs hosted by pantothenate kinase genes, are proposed to regulate cellular lipid metabolism. microRNA-mediated regulation is complex, potentially affecting expression of the host gene, related enzymes within the same pathway, or apparently distinct targets. Using qRT-PCR, we demonstrate that miR-103 and miR-107 expression does not correlate with expression of host pantothenate kinase genes in mouse tissues. The miR-103/7 family thus provides an intriguing model for dissecting microRNA transcription, processing and coordinated function within host genes.

Characterization of the human PANK2 promoter.

Pantothenate kinase 2 (PANK2) is an essential regulatory enzyme in coenzyme A biosynthesis. PANK2 mutations cause pantothenate kinase-associated neurodegeneration (PKAN), which leads to pigmentary retinopathy, progressive dystonia and other abnormalities. Two nearly identical PANK2 isoforms have been described: short PANK2 and mature PANK2, which are processed from a precursor isoform. Since the biological relevance of these isoforms remains unclear, we sought to explore their transcriptional regulation. Here we show that their regulation is distinct and describe a promoter for the short isoform of PANK2. Moreover, we identify potential regulators of PANK2 expression, including NF-Y, FOXN4 and the human heterogeneous nuclear ribonucleoprotein A/B family. These findings validate expression of the short PANK2 isoform and enable predictions about potentially deleterious sequence variants in the regulatory region of this human disease gene.