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

Autor:	Cafournet C; Laboratory for Genetics of Mitochondrial Disorders, Imagine Institute, Université Paris Cité, INSERM U1163, 75015 Paris, France., Zanin S; Laboratory for Genetics of Mitochondrial Disorders, Imagine Institute, Université Paris Cité, INSERM U1163, 75015 Paris, France., Guimier A; Laboratory of Embryology and Genetics of Human Malformations, Imagine Institute, Université Paris Cité, INSERM U1163, 75015 Paris, France.; Genomic Medicine Service for Rare Diseases, APHP.CUP, Necker Enfants Malades Hospital, 75015 Paris, France., Hully M; Pediatric Neurology Department, Necker Enfants Malades Hospital, AP-HP, Institute Imagine, Université Paris Cité, INSERM U1163, 75015 Paris, France., Assouline Z; Department of Genetics, Reference Center for Mitochondrial Diseases (CARAMMEL), Necker Enfants Malades Hospital, 75015 Paris, France., Barcia G; Department of Genetics, Reference Center for Mitochondrial Diseases (CARAMMEL), Necker Enfants Malades Hospital, 75015 Paris, France., de Lonlay P; Reference Center for Inherited Metabolic Diseases, Necker Enfants Malades Hospital, Imagine Institute, Université Paris Cité, INEM-1151, G2M, MetabERN, 75015 Paris, France., Steffann J; Laboratory for Genetics of Mitochondrial Disorders, Imagine Institute, Université Paris Cité, INSERM U1163, 75015 Paris, France.; Department of Genetics, Reference Center for Mitochondrial Diseases (CARAMMEL), Necker Enfants Malades Hospital, 75015 Paris, France., Munnich A; Laboratory for Genetics of Mitochondrial Disorders, Imagine Institute, Université Paris Cité, INSERM U1163, 75015 Paris, France., Bonnefont JP; Laboratory for Genetics of Mitochondrial Disorders, Imagine Institute, Université Paris Cité, INSERM U1163, 75015 Paris, France.; Department of Genetics, Reference Center for Mitochondrial Diseases (CARAMMEL), Necker Enfants Malades Hospital, 75015 Paris, France., Rötig A; Laboratory for Genetics of Mitochondrial Disorders, Imagine Institute, Université Paris Cité, INSERM U1163, 75015 Paris, France., Ruzzenente B; Laboratory for Genetics of Mitochondrial Disorders, Imagine Institute, Université Paris Cité, INSERM U1163, 75015 Paris, France., Metodiev MD; Laboratory for Genetics of Mitochondrial Disorders, Imagine Institute, Université Paris Cité, INSERM U1163, 75015 Paris, France.
Jazyk:	angličtina
Zdroj:	Life (Basel, Switzerland) [Life (Basel)] 2023 Feb 04; Vol. 13 (2). Date of Electronic Publication: 2023 Feb 04.
DOI:	10.3390/life13020445
Abstrakt:	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-tRNA Val -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.
Databáze:	MEDLINE
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