• pantothenate kinase-associated neurodegeneration

This report describes neurodegeneration with brain iron accumulation 1 (NBIA1), which is a subtype of neurodegeneration with brain iron accumulation, NBIA1 exhibits autosomal recessive inheritance. The human gene implicated in this disease is PANK2, which is a pantothenate kinase; a mitochondrially-targeted isoform of this gene is a key regulatory enzyme in the biosynthesis of coenzyme A (CoA). There is a high-scoring Drosophila ortholog, fbl, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. The Dmel\fbl gene is also a high-scoring ortholog of PANK1 and PANK3. A related Drosophila gene, CG5828, is a high-scoring ortholog of PANK4. The human PANK2 gene is also associated with HARP syndrome (MIM:607236).

Multiple different UAS constructs of the human Hsap\PANK2 gene have been introduced into flies, including wild-type and variants carrying mutational lesions associated with NBIA1. When the mitochondrially-targeted isoform of the human gene is expressed in all tissues, heterologous rescue (functional complementation) of the loss-of-function phenotypes of Dmel\fbl, is observed. The human PANK3 and PANK4 genes have also been introduced into flies; expression of either these genes partially rescues loss-of-function phenotypes of Dmel\fbl; male sterility is the only phenotype that is not rescued at all.

Variant(s) implicated in human disease tested (as transgenic human gene, PANK2): the G411R (G230R, G521R) variant form, the T418M (T237M, T528M) variant form, and the S241P (S240P, S351P, S60P) variant form have been introduced into flies. By assaying for degree of heterologous rescue, the residual activity of these variants was assessed.

The Drosophila fblgene encodes several isoforms of pantothenate kinase products, one of which localizes to mitochondria and the others to the cytosol (FBrf0209004). Loss-of-function mutants typically die during the pupal stage with a few escapers that eclose and survive several additional days; the rare survivors exhibit impaired locomotion ability, infertility and neurodegeneration in the brain and retina. Pharmaceuticals that enhance pyruvate dehydrogenase (PDH) activity were tested (by feeding) and found to rescue the reduced viability phenotype; see FBhh0001238 for the rationale behind these experiments.

Animals heterozygous for a hypomorphic allele of fbl, were assessed for levels of a number of biologically relevant metals. Surprisingly, no change in iron levels was observed, relative to control animals. However, a significant three-fold increase in total zinc levels was observed. No significant changes in total copper or manganese levels (normally low) were observed.

A single genetic interaction has been described for Dmel\fbl; see the fbl gene report.

[updated Aug. 2020 by FlyBase; FBrf0222196]