The relationship between MRPL39 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 29, 2024. The MRPL39 gene encodes the mitochondrial ribosomal protein L39, one of 52 mitochondrial large ribosomal protein subunits that form the mitochondrial ribosome.
MRPL39 was first reported in relation to autosomal recessive primary mitochondrial disease in 2023 (PMID:18771761), in three affected individuals presenting with a broad phenotype spectrum of severe disease including Leigh syndrome spectrum (LSS). Clinical features included developmental delay, hypotonia, hypertrophic cardiomyopathy, feeding difficulty and faltering growth, together with brain abnormalities detected by MRI and elevate blood lactate. The age of onset ranged from birth to early infancy and cases showed variability in the severity of the clinical course. While various names have been given to the constellation of features seen in those with MRPL39-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MRPL39 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.
Evidence supporting the gene-disease relationship between MRPL39 and primary mitochondrial disease includes case-level data and experimental data. This curation includes four unique variants in three probands from one publication (PMID: 18771761). Variant types included one missense, one frameshift, and two splice region variants. Loss of function is implicated as the mechanism of disease.
This gene-disease association is also supported by known biochemical function and functional alteration observed in fibroblasts from affected individuals (PMIDs: 33340416; 18771761).
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 January 29, 2024 (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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