Drosophila assays of movement and mitochondria included in study of an autosomal dominant spastic paraplegia and dystonia

Mov Disord. 2021 Oct 11. doi: 10.1002/mds.28821

A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia

Neilson DE, Zech M, Hufnagel RB, Slone J, Wang X, Homan S, Gutzwiller LM, Leslie EJ, Leslie ND, Xiao J, Hedera P, LeDoux MS, Gebelein B, Wilbert F, Eckenweiler M, Winkelmann J, Gilbert DL, Huang T

Abstract:

BACKGROUND: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31.

OBJECTIVE: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia.

METHODS: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function.

RESULTS: Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility.

CONCLUSION: A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.

DOI: 10.1002/mds.28821
PMID: 34636445

Clocks & Neurodisease. Breaking Report.

This study looks at the effect of genetically disrupting circadian rhythms on neurodegeneration, and finds functional ties between the two.

Krishnan N, Rakshit K, Chow ES, Wentzell JS, Kretzschmar D, Giebultowicz JM. Loss of circadian clock accelerates aging in neurodegeneration-prone mutants. Neurobiol Dis. 2012 Mar;45(3):1129-35. PubMed PMID: 22227001; PubMed Central PMCID: PMC3291167.

Mutations in swi and sws are used in the study to model neurodegeneration.

The swi gene appears not to have been well conserved (no strong-scoring matches at DIOPT for example). By contrast, the sws gene has been conserved. The fly sws gene is related to the human gene PNPLA6 (also called NTE; Entrez Gene ID 10908). PNPLA6 is associated with spastic paraplegia 39, one of a group of spastic paraplegias. According to the literature summary at Entrez Gene, the normal role of the PNPLA6 protein is as a phopholipase that deacetyates intracellular phophatidylcholine, producing glycerophophocholine.

Mutations in per are used in the study to disrupt circadian rhythms.

The fly per gene has at least 3 putative orthologs in the human genome, PER1, PER2 and PER3. According to OMIM, mutations in PER2 are associated with familial advanced sleep phase syndrome.