The relationship between MRPS25 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 20, 2024. The MRPS25 gene encodes the mitochondrial ribosomal protein S25, a component of the small subunit of the mitochondrial ribosome.
The first and only report of MRPS25 in relation to autosomal recessive primary mitochondrial disease was in 2019 (PMID: 31039582), in a 25-year-old man with a history of chorea, dystonia, partial agenesis of corpus callosum, adrenal insufficiency, short stature, and microcephaly. Muscle biopsy in childhood was originally unremarkable but repeat biopsy at 19 years old showed COX-negative fibers and reduced activities of the mitochondrial respiratory chain enzymes. He had a homozygous missense variant in MRPS25. While various names could be given to the constellation of features seen in those with MRPS25-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MRPS25 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included the one missense variant noted above in one case in one publication (PMID: 31039582).
The mechanism of disease is loss of function This gene-disease association is also supported by the known biochemical function of MRPS25 in mitochondrial translation and rescue studies performed in patient cells (PMID: 31039582).
In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 20, 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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