Drosophila model reveals mechanistic insights into the human disease-associated gene PNPLA6 and disease-associated variants

Sunderhaus ER, Law AD, Kretzschmar D. Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila. Front Neurosci. 2019 Nov 6;13:1207. PMID:
31780887; PMCID: PMC6852622.

From the abstract: "Mutations in patatin-like phospholipase domain-containing protein 6 (PNPLA6) have been linked with a number of inherited diseases with clinical symptoms that include spastic paraplegia, ataxia, and chorioretinal dystrophy. PNPLA6 is an evolutionary conserved protein whose ortholog in Drosophila is Swiss-Cheese (SWS). ... disease-causing point mutations are found in homozygous patients, with some localized in the phospholipase domain while others are in a region that contains several cNMP binding sites. To investigate how different mutations affect the function of PNPLA6 in an in vivo model, we expressed them in the Drosophila sws1 null mutant. Expressing wild-type PNPLA6 suppressed the locomotion and degenerative phenotypes in sws 1 and restored lipid levels, confirming that the human protein can replace fly SWS. In contrast, none of the mutant proteins restored lipid levels, although they suppressed the behavioral and degenerative phenotypes, at least in early stages. These results show that these mutant forms of PNPLA6 retain some biological function, indicating that disruption of lipid homeostasis is only part of the pathogenic mechanism. ..."

Flies used in international effort to identify mutations associated with a recessive form of ataxia or spastic paraplegia

Seong E, Insolera R, Dulovic M, Kamsteeg EJ, Trinh J, Brüggemann N, Sandford E, Li S, Ozel AB, Li JZ, Jewett T, Kievit AJA, Münchau A, Shakkottai V, Klein C, Collins CA, Lohmann K, van de Warrenburg BP, Burmeister M. Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects. Ann Neurol. 2018 Jun;83(6):1075-1088. PubMed PMID: 29604224; PubMed Central PMCID: PMC6105379.

From the abstract: "To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias, and spastic paraplegia. ... In an international collaboration, we independently performed exome sequencing in 7 families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knockout model and investigated mitochondrial function in patient-derived fibroblast cultures. ... Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders."

See also:

Fogel BL. Collaborative science unites researchers and a novel spastic ataxia gene. Ann Neurol. 2018 Jun;83(6):1072-1074. PubMed PMID: 29908061; PubMed Central PMCID: PMC6105536.