Novel ELAC2 Mutations in Individuals Presenting with Variably Severe Neurological Disease in the Presence or Absence of Cardiomyopathy

Abstract

Transcription of mitochondrial DNA generates long polycistronic precursors whose nucleolytic cleavage yields the individual mtDNA-encoded transcripts. In most cases, this cleavage occurs at the 5′- and 3′-ends of tRNA sequences by the concerted action of RNAseP and RNaseZ/ELAC2 endonucleases, respectively. Variants in the ELAC2 gene have been predominantly linked to severe to mild cardiomyopathy that, in its milder forms, is accompanied by variably severe neurological presentations. Here, we report five patients from three unrelated families. Four of the patients presented mild to moderate cardiomyopathy and one died at 1 year of age, one patient had no evidence of cardiomyopathy. The patients had variable neurological presentations that included intellectual disability, ataxia, refractory epilepsy, neuropathy and deafness. All patients carried previously unreported missense and nonsense variants. Enzymatic analyses showed multiple OXPHOS deficiencies in biopsies from two patients, whereas immunoblot analyses revealed a decreased abundance of ELAC2 in fibroblasts from three patients. Northern blot analysis revealed an accumulation of unprocessed mt-tRNAVal-precursor consistent with the role of ELAC2 in transcript processing. Our study expands the genetic spectrum of ELAC2-linked disease and suggests that cardiomyopathy is not an invariably present clinical hallmark of this pathology.

Structural basis for human mitochondrial tRNA maturation

“…14). Most of these mutations cause defects in mitochondrial tRNA maturation and respiratory chain deficiency in patients [49][50][51][52][53][54][55][56] . For TRMT10C, the diseaseassociated mutations, R181 and L182, are involved in the stabilisation of the distinctive anticodon loop conformation observed in all structures of tRNA bound to the TRMT10C/SDR5C1 complex, while T272 is located in a large loop and makes hydrophobic contact with Y244, a conserved residue of TRMT10C.…”

Advances in the Structural and Functional Understanding of m1A RNA Modification

“…They affect binding and m 1 R9 methylation by TRMT10C and TRMT10C-mediated tRNA-processing by MRPP3 . Impaired processing of mt-tRNAs has a detrimental effect on mt gene expression and the assembly of mt ribosomes. , As a consequence, mutations that disturb mt-tRNA structures or any step of mt-tRNA maturation are linked to severe human diseases. − Most of these mutations cause defects in mt-tRNA maturation and respiratory chain deficiency in patients. ,,,− The disease-associated mutations of TRMT10C, R181 and L182, are involved in the stabilization of the distinctive anticodon loop conformation observed in all structures of tRNA bound to the TRMT10C/SDR5C1 complex . Hypo m 1 A modification in tRNAs has also been proposed to play a role in Alzheimer’s disease pathogenesis …”

Illuminating mitochondrial translation through mouse models

“…The RNase P complex (composed of MRPP1/TRMT10C, MRPP2/HSD17B10 and MRPP3/PRORP) cleaves the 5′ ends of tRNAs [ 48 , 49 ] and the RNase Z, ELAC2, cleaves the 3′ ends [ 50 ], thereby releasing the individual mt-mRNAs, mt-tRNAs and mt-rRNAs. Pathogenic mutations that cause mitochondrial disease have been identified in all of the mtRNA processing components [ 51–55 ], and mouse deletions of Mrpp2, Mrpp3 and Elac2 have been generated [ 49 , 50 , 56 ]. Like POLRMT and TEFM, MRPP3/PRORP and ELAC2 are essential proteins with non-redundant functions that cause very early cardiomyopathy and premature death in mice that model that seen in the patient mutations.…”