The relationship between MRPL44 and autosomal recessive primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 7, 2022. The MRPL44 gene encodes mitochondrial ribosomal protein L44, which is a component of the large subunit (39S) of the mitochondrial ribosome.
The *MRPL44 *gene was first reported in relation to primary mitochondrial disease in 2013 (PMID: 23315540). While various names have been given to the constellation of features seen in those with MRPL44-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MRPL44 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 unique variants (3 missense, 1 frameshift) identified in six unrelated cases from four publications (PMIDs: 23315540, 25797485, 34140213, 33742325). The mechanism of pathogenicity appears to be loss of function. Of note, the c.467T>G, p.Leu156Arg variant has been identified in every case reported to date and may be a founder variant in the European population, although this has not been confirmed. This gene-disease relationship is also supported by a biochemical function (mitochondrial translation) shared with other genes associated with primary mitochondrial disease, functional alteration studies in patient cells showing impaired synthesis of mitochondrial proteins, and rescue of the mitochondrial protein levels and large mitochondrial ribosomal subunit assembly in patient cells following expression of the wild type protein (PMIDs: 33340416, 33742325, 23315540).
In summary, there is definitive evidence to support the relationship between MRPL44 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 7, 2022 (SOP Version 9).
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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