Infantile Encephaloneuromyopathy and Defective Mitochondrial Translation Are Due to a Homozygous RMND1 Mutation

Defects of mitochondrial protein synthesis are clinically and genetically heterogeneous. We previously described a male infant who was born to consanguineous parents and who presented with severe congenital encephalopathy, peripheral neuropathy, myopathy, and lactic acidosis associated with deficiencies of multiple mitochondrial respiratory-chain enzymes and defective mitochondrial translation. In this work, we have characterized four additional affected family members, performed homozygosity mapping, and identified a homozygous splicing mutation in the splice donor site of exon 2 (c.504+1G>A) of RMND1 (required for meiotic nuclear division-1) in the affected individuals. Fibroblasts from affected individuals expressed two aberrant transcripts and had decreased wild-type mRNA and deficiencies of mitochondrial respiratory-chain enzymes. The RMND1 mutation caused haploinsufficiency that was rescued by overexpression of the wild-type transcript in mutant fibroblasts; this overexpression increased the levels and activities of mitochondrial respiratory-chain proteins. Knockdown of RMND1 via shRNA recapitulated the biochemical defect of the mutant fibroblasts, further supporting a loss-of-function pathomechanism in this disease. RMND1 belongs to the sif2 family, an evolutionary conserved group of proteins that share the DUF155 domain, have unknown function, and have never been associated with human disease. We documented that the protein localizes to mitochondria in mammalian and yeast cells. Further studies are necessary for understanding the function of this protein in mitochondrial protein translation.

Marriott Mitochondrial Disorder Clinical Research Fund

Marriott Mitochondrial Disorder Clinical Research Fund

National Institute of Health (NIH) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)

National Institute of Health (NIH) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [K23 HD065871]

NIH from the NICHD [R01 HD057543, R01 HD056103]

NIH from the NICHD

Office of Dietary Supplements

Office of Dietary Supplements

National Institute of Neurological Disorders and Stroke [U54NS078059]

National Institute of Neurological Disorders and Stroke

Muscular Dystrophy Association

Muscular Dystrophy Association

Fundacao Amparo a Pesquisa Sao Paulo

Fundacao Amparo a Pesquisa Sao Paulo

American Heart Association

American Heart Association [0930151N]

American Society of Nephrology

American Society of Nephrology

NICHD

NICHD