RMND1 – Combined Oxidative Phosphorylation Deficiency 11

RMND1 encodes the required for meiotic nuclear division 1 homolog, a mitochondrial inner membrane protein essential for proper assembly and function of the oxidative phosphorylation (OXPHOS) machinery. Biallelic RMND1 variants cause Combined Oxidative Phosphorylation Deficiency 11 (MONDO:0013969), an autosomal recessive multisystem disorder characterised by lactic acidosis, encephalopathy, renal failure, hearing loss, and early mortality. The inheritance is uniformly autosomal recessive, with affected individuals inheriting two pathogenic RMND1 alleles.

Genetic evidence includes 49 unrelated probands carrying biallelic RMND1 variants in a comprehensive literature review (PMID:39634248). Segregation analysis documented 4 additional affected relatives in consanguineous pedigrees confirming co-segregation of RMND1 variants with disease (PMID:23022099). The variant spectrum encompasses missense changes (e.g., c.713A>G (p.Asn238Ser)), splicing defects (c.504+1G>A), frameshifts (c.1003del), and stop-extension alleles (c.1349G>C).

The recurrent missense variant c.713A>G (p.Asn238Ser) represents the most frequent allele in 27% of cases, associated with reduced mortality, whereas the stop-extension c.1349G>C allele correlates with increased cardiac involvement and worse survival metrics (PMID:39634248). These genotype–phenotype correlations support variant-specific prognostication and inform genetic counselling.

Functional studies demonstrate that RMND1 deficiency leads to assembly defects across multiple OXPHOS complexes and a profound mitochondrial translation defect. Blue native PAGE and immunoblot analyses revealed loss of a ~240 kDa RMND1 homopolymeric complex in patient fibroblasts, with concurrent decreases in mitochondrial ribosomal subunits (PMID:23022098).

Rescue experiments using retroviral expression of wild-type RMND1 cDNA restored complex assembly and translation competence, whereas siRNA- or shRNA-mediated knockdown recapitulated the biochemical defect, confirming a loss-of-function mechanism (PMID:23022098; PMID:23022099).

Integration of genetic and experimental findings establishes a definitive gene–disease relationship. RMND1 testing should be incorporated into diagnostic panels for early detection of OXPHOS deficiency, guiding timely interventions and family counselling.

References

• Molecular syndromology • 2024 • RMND1 Mutation Case Report and Literature Review PMID:39634248
• American Journal of Human Genetics • 2012 • An RMND1 Mutation causes encephalopathy associated with multiple oxidative phosphorylation complex deficiencies and a mitochondrial translation defect PMID:23022098
• American Journal of Human Genetics • 2012 • Infantile encephaloneuromyopathy and defective mitochondrial translation are due to a homozygous RMND1 mutation PMID:23022099

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