TRMT10C – mitochondrial disease

TRMT10C encodes mitochondrial RNase P protein 1 (MRPP1), a core component of the mt‐RNase P complex responsible for 5′ end cleavage of mt‐tRNA precursors and m¹R9 methylation. Biallelic TRMT10C variants were identified in two unrelated infants presenting with neonatal lactic acidosis, profound hypotonia, feeding difficulties, and sensorineural hearing loss, culminating in death by 5 months of age. These clinical and molecular findings establish a clear link between MRPP1 deficiency and a severe early‐onset mitochondrial disease (PMID:27132592).

Whole‐exome sequencing revealed compound heterozygous c.542G>T (p.Arg181Leu) and c.814A>G (p.Thr272Ala) variants in Subject 1 and homozygous c.542G>T (p.Arg181Leu) in Subject 2, all altering conserved residues in MRPP1’s catalytic or stability domains (PMID:27132592). Parental segregation confirmed recessive inheritance with carriers phenotypically normal, and no additional affected relatives were reported. These two probands represent independent occurrences, providing genetic evidence of TRMT10C’s role in mitochondrial disease etiology.

All reported variants are missense and predicted to disrupt MRPP1 stability rather than methyltransferase activity. No truncating or splice‐site alleles have been described, and no recurrent or founder variants beyond c.542G>T have been observed. Carrier frequency and broader phenotypic variability remain undefined due to the rarity of cases.

Functional studies in patient fibroblasts demonstrated markedly reduced MRPP1 protein levels and accumulation of unprocessed mt‐RNA precursors, correlating with impaired mitochondrial translation and respiratory chain deficiencies. mt‐tRNA primary transcript processing assays and mitochondrial protein synthesis rates were significantly decreased in mutant cells (PMID:27132592).

Lentiviral transduction of wild‐type TRMT10C into patient fibroblasts fully rescued mt‐RNA processing and mitochondrial translation defects, confirming the pathogenicity of the identified alleles and implicating loss of MRPP1 stability as the disease mechanism. Rescue experiments support haploinsufficiency rather than a dominant‐negative effect.

No conflicting or refuting studies have been reported. The combination of two unrelated probands with biallelic TRMT10C variants and comprehensive rescue of cellular phenotypes meets ClinGen criteria for a Moderate gene–disease association. Further case ascertainment will refine genotype–phenotype correlations.

Key Take-home: Biallelic TRMT10C missense variants cause an autosomal recessive, early‐onset mitochondrial disease via impaired mt‐tRNA processing, providing a molecular target for diagnostic confirmation and future therapeutic exploration.

References

• American journal of human genetics • 2016 • Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies. PMID:27132592

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