MRPS34 – Leigh syndrome

This summary evaluates the association between MRPS34 and Leigh syndrome. The evidence includes both single case reports and multi‐patient studies that demonstrate an autosomal recessive inheritance. A case report identified a novel pathogenic variant and provided proof that reduced MRPS34 levels result in OXPHOS deficiency, explaining the patient’s motor delay and distinct neuroimaging findings (PMID:34938649). This report involved 1 proband and represents vital evidence in establishing the gene-disease link (PMID:34938649). Furthermore, the clinical presentation is consistent with hallmark symptoms such as motor delay (HP:0001270). Overall, these findings underscore the clinical relevance of MRPS34 in the pathogenesis of Leigh syndrome.

In a multi‐patient study, four distinct pathogenic mutations in MRPS34 were identified in 6 subjects from 4 unrelated families (PMID:28777931). The study reported autosomal recessive segregation including affected sibling pairs. This multi‐patient evidence reinforces the association, with segregation data supporting that the variants co‐segregate with the typical disease phenotype. In addition, the observed mutation spectrum, which includes both splice-site and coding missense as well as loss-of-function variants, consolidates the genotype–phenotype correlation in Leigh syndrome. Such robust segregation and multiple case evidences contribute significantly to the gene-disease validity.

Genetic evidence is further bolstered by the variant data. Among the reported mutations, the missense variant c.37G>A (p.Glu13Lys) is highlighted as a representative coding change with clear functional repercussions (PMID:28777931). Additional variants, including a nonsense variant c.94C>T (p.Gln32Ter), further represent the mutation spectrum, with all variants segregating in an autosomal recessive manner. The aggregated data from 7 probands (1 from the novel case and 6 from multi‐patient studies) provide a compelling genetic basis. Overall, the genetic evidence is consistent with pathogenic alleles causing a reduction in functional MRPS34 protein levels.

Functional studies have clearly demonstrated that pathogenic MRPS34 variants impair the stability of the small mitoribosomal subunit. Assays, including quantitative proteomics and rescue experiments via lentiviral‐mediated expression of wild‐type MRPS34, have confirmed reduced synthesis of mitochondrial OXPHOS subunits and monosome assembly defects (PMID:28777931). Furthermore, the loss of function in MRPS34 links mechanistically to the observed OXPHOS enzyme deficiency seen in Leigh syndrome patients. These experimental results, which are concordant with the genetic findings, reinforce a mechanism of haploinsufficiency contributing to disease. Thus, the functional data provide a strong complementary facet to the genetic evidence.

While the discussed studies are coherent, it is noteworthy that the novel case report and multi‐patient study together exceed the maximum possible ClinGen scoring threshold. No significant conflicting evidence has been reported, although further studies might better delineate the full phenotypic spectrum. The combined evidence supports a strong gene-disease association, with multi-family segregation and detailed functional assessments confirming the impact of MRPS34 alterations. In summary, both clinical and experimental data make a compelling argument for the diagnostic utility of targeting MRPS34 variants in Leigh syndrome.

Key take‑home message: The strong association between MRPS34 variants and Leigh syndrome, validated by consistent genetic segregation and functional impairment data, supports its use in diagnostic decision‑making and therapeutic targeting.

References

• Molecular genetics and metabolism reports • 2022 • A novel MRPS34 gene mutation with combined OXPHOS deficiency in an adult patient with Leigh syndrome (PMID:34938649)
• American journal of human genetics • 2017 • Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome (PMID:28777931)

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