好色先生

好色先生

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Abstract Details

Infantile Encephaloneuromyopathy and Defective Mitochondrial Translation Are Due to a Homozygous RMND1 Mutation
Child Neurology/Developmental Neurobiology
P03 - (-)
010
BACKGROUND: Alterations of mitochondrial protein synthesis caused by mutation in several nuclear genes frequently present as lethal encephalopathies associated with combined deficiencies of respiratory-chain and oxidative-phosphorylation (OXPHOS) enzymes. We evaluated a consanguineous family with four children who presented with neonatal encephaloneuromyopathy and lactic acidosis.
DESIGN/METHODS: High density genome-wide genotyping of four affected and eight unaffected relatives identified a single region of homozygosity shared by all affected individuals. Exons of the genes in the candidate locus were sequenced by dideoxy DNA sequencing. To confirm the pathogenicity of the mutation, the wild type protein was overexpressed in the proband fibroblasts, and shRNA-mediated knockdown of the protein in Hela cells were performed, and respiratory-chain enzymes activities, steady-state level, and mitochondrial proteins synthesis were evaluated.
RESULTS: A homozygous c.504+1G>A splice donor mutation in the gene encoding RMND1 was found. RMND1 is a mitochondrial protein and belongs to the sif2 family, a conserved group of proteins sharing the DUF155 domain. Mutant fibroblasts have decreased wild type transcript, and two aberrant transcipts. Biochemical activities and steady-state level of respiratory-chain enzymes increased after RMND1 overexpression. Depletion of RMND1 by shRNA decreased OXPHOS activities, steady-state levels, and mitochondrial protein synthesis.
CONCLUSIONS: We identified the first human mutation affecting a DUF155 protein in a family with a severe autosomal-recessive mitochondrial translation defect. Further studies are necessary to understand the function of RMND1 and its role in mitochondrial protein synthesis.
Authors/Disclosures
Beatriz Garcia-Diaz
PRESENTER 		No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Rita Horvath, MD (Jahn F Hospital, Dept Neurology) No disclosure on file
John T. Kissel, MD, FAAN Dr. Kissel has nothing to disclose.
No disclosure on file
No disclosure on file
Salvatore DiMauro, MD (Columbia University Medical Center) No disclosure on file
Darryl C. De Vivo, MD, FAAN (Columbia University) Dr. De Vivo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen and Novartis. Dr. De Vivo has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Aspa Therapeutics.
No disclosure on file
Michio Hirano, MD, FAAN (Columbia University Medical Center) Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB Biopharma SRL. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Precision Biosciences. Dr. Hirano has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Biopharma SRL. Dr. Hirano has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Apollo Communication. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Envision Communications. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for 好色先生. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Cure SMA. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Muscular Dystrophy Association. The institution of Dr. Hirano has received research support from UCB. The institution of Dr. Hirano has received research support from Cyclerion. The institution of Dr. Hirano has received research support from Astellas. The institution of Dr. Hirano has received research support from Tisento Therapeutics. The institution of Dr. Hirano has received research support from Stealth Biotherapeutics. The institution of Dr. Hirano has received research support from Abliva. Dr. Hirano has received intellectual property interests from a discovery or technology relating to health care. Dr. Hirano has received intellectual property interests from a discovery or technology relating to health care. Dr. Hirano has received personal compensation in the range of $0-$499 for serving as a Study Section Reviewer with NIH. Dr. Hirano has a non-compensated relationship as a Research Advisory Board member with Muscular Dystrophy Association that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific and Medical Advisory Board member with United Mitochondrial Disease Foundation that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific Advisory Board member with Barth Syndrome Foundation that is relevant to AAN interests or activities.
Catarina Quinzii Hirano, MD No disclosure on file