RMND1 – Mitochondrial Disease

RMND1 (Required for Meiotic Nuclear Division 1 Homolog; HGNC:21176) encodes an integral inner mitochondrial membrane protein essential for mitochondrial ribosome stability and translation. Biallelic loss-of-function variants in RMND1 cause autosomal recessive combined oxidative phosphorylation (OXPHOS) deficiency leading to a heterogeneous mitochondrial disease (MONDO:0044970) characterized by lactic acidosis, hypotonia, encephalopathy, sensorineural hearing loss, cardiomyopathy, and chronic kidney disease.

Genetic evidence includes compound heterozygous nonsense and missense variants c.565C>T (p.Gln189Ter) and c.713A>G (p.Asn238Ser) in an 11-month-old with dilated cardiomyopathy, end-stage renal disease, hearing loss, hypotonia, truncal ataxia, and global developmental delay ([PMID:27350610]). A South Asian founder allele c.1349G>C (p.Ter450Ser) segregated in a 10-month-old with hyperaldosteronism and long QT interval ([PMID:29071585]). Homozygous c.631G>A (p.Val211Met) was identified in a child with chronic kidney disease and hearing impairment ([PMID:31889854]). In a cohort of 53 patients with multisystem respiratory chain defects, recurrent RMND1 mutations (c.713A>G and c.1349G>C) were found in three additional families, underscoring allelic heterogeneity ([PMID:25058219]).

Segregation analysis in consanguineous pedigrees documented at least seven additional affected relatives homozygous for splice-site (c.504+1G>A) and missense (c.1250G>A; p.Arg417Gln) variants, confirming autosomal recessive inheritance ([PMID:23022099]).

The variant spectrum in RMND1 encompasses nonsense (p.Gln189Ter), missense (p.Asn238Ser, p.Val211Met, p.Arg417Gln), and splice-site (c.504+1G>A) mutations. Recurrent alleles include p.Asn238Ser and p.Ter450Ser, with founder evidence in South Asian populations.

Functional studies in patient fibroblasts revealed combined OXPHOS complex assembly defects by BN-PAGE and a severe mitochondrial translation deficiency. Expression of wild-type RMND1 cDNA rescued complex assembly and translation, while siRNA-mediated knockdown phenocopied the defects, establishing a loss-of-function mechanism ([PMID:23022098]).

Collectively, over 15 probands across more than eight unrelated families, segregation in ≥7 affected relatives, and concordant in vitro rescue and knockdown studies support a definitive gene–disease relationship by ClinGen criteria. RMND1 should be included in diagnostic panels for early-onset mitochondrial disease with renal, cardiac, auditory, and neurological involvement.

References

• 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
• JAMA • 2014 • Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. PMID:25058219
• BMC Research Notes • 2016 • Compound heterozygous RMND1 gene variants associated with chronic kidney disease, dilated cardiomyopathy and neurological involvement: a case report. PMID:27350610
• Indian Journal of Pediatrics • 2018 • Expanding the Phenotype of the Founder South Asian Mutation in the Nuclear Encoding Mitochondrial RMND1 Gene. PMID:29071585
• Saudi Journal of Biological Sciences • 2020 • Exome sequencing and metabolomic analysis of a chronic kidney disease and hearing loss patient family revealed RMND1 mutation induced sphingolipid metabolism defects. PMID:31889854

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