The relationship between ATP5MK and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 15, 2024. The ATP5MK gene (alternate names include ATP5MD, USMG5, and DAPIT) encodes a subunit of the mitochondrial ATP synthase, also known as complex V of the oxidative phosphorylation system. Defects of this protein lead to a reduction of ATP synthesis.
The first and only report of ATP5MK-related autosomal recessive primary mitochondrial disease was in 2018 (PMID: 29917077), in three probands from unrelated Ashkenazi Jewish families. The three probands all presented with Leigh syndrome spectrum disorder and were homozygous for the same intronic variant, c.87+1G>C, which impacts splicing and is proposed to be a founder variant. While various names have been given to the constellation of features seen in those with ATP5MK-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the ATP5MK phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, ATP5MK was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on July 13, 2020 (SOP V7), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes the three cases included in the LSS curation.
Evidence supporting this gene-disease relationship includes case-level data and experimental data.
The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of ATP5MK as a structural subunit of complex V, as well as functional alteration in HeLa cells (PMID: 21345788), Drosophila models (PMID: 29234032), and rescue in patient cells (PMID: 29917077). Of note, a mouse model exists but was not included in this curation due to limited phenotype information and incomplete penetrance (PMID: 28650483).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 15, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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