The relationship between MRPS28 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 20, 2024. The MRPS28 gene encodes the mitochondrial ribosomal protein S28, a component of the small subunit of the mitochondrial ribosome.
The first and only report of MRPS28 in relation to autosomal recessive primary mitochondrial disease was in 2019 (PMID: 30566640; case was first described in PMID: 8989468), in a 30-year-old man who presented in infancy with failure to thrive, hypoglycemia, dysmorphic facial features, sensorineural hearing loss, and cataracts. By age 24 years, he had elevated liver enzymes and globus pallidus lesions with cerebellar atrophy noted on brain imaging. Muscle biopsy showed reduced activities of the mitochondrial respiratory chain enzymes. He had compound heterozygous (missense and frameshift) variants in MRPS28. While various names could be given to the constellation of features seen in those with MRPS28-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MRPS28 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 two variants noted above in one case from one publication (PMID: 30566640).
The mechanism of disease is loss of function This gene-disease association is also supported by the known biochemical function of MRPS28 in mitochondrial translation, and rescue studies performed in patient cells (PMID: 30566640).
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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