LRPPRC – Leigh syndrome

The mitochondrial gene LRPPRC encodes a leucine-rich pentatricopeptide repeat–containing protein that forms a ribonucleoprotein complex with SLIRP to stabilize mature mitochondrial mRNAs. Pathogenic variants impair posttranscriptional regulation of oxidative phosphorylation transcripts, leading to tissue-specific cytochrome c oxidase (COX) deficiency and the French-Canadian subtype of Leigh syndrome, a progressive neurodegenerative disorder (MONDO:0009723).

Autosomal recessive inheritance is supported by a founder missense variant, c.1061C>T (p.Ala354Val), in French-Canadian patients (PMID:20200222), and by ten additional probands from seven unrelated families of UK-Caucasian, Pakistani, Indian, Turkish and Iraqi origin (PMID:26510951). A novel homozygous splice-donor variant c.469+1G>A segregated with disease in a Saudi family, confirming recessive transmission (PMID:38046674).

The variant spectrum includes the recurrent founder missense c.1061C>T (p.Ala354Val) and multiple loss-of-function alleles—splice-site changes, small insertions/deletions and frameshifts—distributed across the coding sequence. The selected representative variant is c.1061C>T (p.Ala354Val).

Functional assays demonstrate that LRPPRC deficiency reduces steady-state levels of most mitochondrial mRNAs without affecting rRNAs or tRNAs, causing isolated COX assembly defects in patient fibroblasts and generalized OXPHOS assembly defects upon siRNA knockdown (PMID:20200222). Patient skeletal muscle and fibroblast studies show decreased complex IV activity, abnormal COX assembly and reduced transcript levels (PMID:26510951). Treatment of LSFC fibroblasts with low-concentration methylene blue fully restores metabolic activity and ATP content in cells homozygous or compound heterozygous for A354V and other variants (PMID:22202226).

No studies have refuted the role of LRPPRC in Leigh syndrome. Exploratory sequencing in Parkinson disease cohorts identified only synonymous and noncoding LRPPRC variants that did not alter protein abundance or function (PMID:21437181).

Collectively, autosomal recessive LRPPRC variants cause Leigh syndrome through loss of mRNA stability and COX deficiency. Genetic and experimental concordance across diverse populations support a strong gene–disease association. Key Take-home: LRPPRC sequencing and functional assays guide molecular diagnosis and may inform potential therapeutic strategies such as methylene blue in Leigh syndrome.

References

• Molecular biology of the cell • 2010 • LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria. PMID:20200222
• Brain • 2015 • LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population. PMID:26510951
• Frontiers in pediatrics • 2023 • A novel homozygous splice donor variant in the LRPPRC gene causing Leigh syndrome with epilepsy, a French-Canadian disorder in a Saudi family: case report. PMID:38046674
• Journal of pharmacy & pharmaceutical sciences • 2011 • Low-concentration methylene blue maintains energy production and strongly improves survival of Leigh syndrome French Canadian skin fibroblasts. PMID:22202226

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