Submission Details

The relationship between MRPL3 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 15, 2022. The MRPL3 gene encodes the mitochondrial ribosomal protein L3, a large mitochondrial ribosomal subunit protein.

The MRPL3 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2011 (PMID: 21786366). While various names could be given to the constellation of features seen in those with MRPL3-related disease (including combined oxidative phosphorylation deficiency 9), pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MRPL3 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 four variants (one missense variant present in the compound heterozygous state in two probands, another missense variant present in the homozygous state in one proband, one frameshift, and one deletion) identified in three probands from three publications (PMID: 21786366, 27815843, 34008913). Age of onset in affected individuals ranged from the first day of life to six months old and outcomes ranged from death by 11 months old to alive at 11 years old. Features seen in affected individuals include severe infantile hypertrophic cardiomyopathy, hepatopathy, failure to thrive/feeding difficulty, and sensorineural hearing loss. Fibroblast testing showed a combined oxidative phosphorylation deficiency and a marked decrease of fully assembled complexes I, IV, and V, with normal complex II). Brain imaging was consistent with Leigh syndrome in one proband and an elevated lactate peak on brain MRS was seen in two probands. Laboratory abnormalities include hypoglycemia, elevated plasma alanine, and lactic acidosis. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function (mitochondrial translation) shared with other genes associated with primary mitochondrial disease, functional alteration in patient cells, and model systems (PMIDs: 21786366, 32341096).

In summary, there is moderate 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 August 15, 2022 (SOP Version 9).