Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

Journal article

183 p.Among the hundreds of nuclear-encoded components of mitochondria that have been linked to human disease, mutations in the ATAD3 gene cluster have emerged as one of the most frequent in recent years. The ATAD3 locus encodes three highly homologous mitochondrial transmembrane proteins that are members of the AAA+ protein family. ATAD3 has been implicated in mitochondrial DNA and cholesterol metabolism, as well as mitochondrial morphology and ultrastructure. In this thesis, several new ATAD3 mutants have been characterized and have been studied in cultured human cells and in a Drosophila model. These investigations have identified elevated free and membrane-embedded cholesterol as core features of pathological ATAD3 variants. Thus, this is a recurring cellular phenotype characteristic of mutant ATAD3, and as such, it represents a valuable new diagnostic tool, in combination with ATAD3 protein separation and immunodetection. Moreover, a model of the molecular mechanism of the disease has been proposed in which the high level of cholesterol results in cholesterol aggregates in membranes provoking an extraordinary expansion of lysosomes to digest the aberrant membranes. Multiple strategies aimed at modulating cholesterol and lipid metabolism increased cholesterol levels and none decreased it, which might exacerbate rather than mitigate the ATAD3 cellular phenotypes. However, sphingosine supplementation distinguished the ATAD3 mutants from control cells, which identifies an important future avenue for developing therapies

Authors: Yap, ZY; Park, YH; Wortmann, SB; Gunning, AC; Ezer, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Genome Medicine
• Volume: 13
• Issue: 1
• Pages: 55-55
• Article number: 55
• Publication date: 2021-04-12
• DOI: 10.1186/s13073-021-00873-3
• EISSN: 1756-994X
• ISSN: 1756-994X
• Language: English
• Keywords: Mitochondrial Encephalomyopathies; Allele; Genetics; Hypotonia; Missense mutation; Null allele; Gene; Frameshift mutation; Mitochondrial DNA; Loss function; Phenotype; Exome sequencing; Mitochondrial myopathy; Biology