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

• Published in: American journal of human genetics 2012-10, Vol.91 (4), p.729-736
• Main Authors: GARCIA-DIAZ, Beatriz, BARROS, Mario H, DE VIVO, Darryl C, SHOKR, Aly, HIRANO, Michio, QUINZII, Catarina M, SANNA-CHERCHI, Simone, EMMANUELE, Valentina, AKMAN, Hasan O, FERREIRO-BARROS, Claudia C, HORVATH, Rita, TADESSE, Saba, EL GHARABY, Nader, DIMAURO, Salvatore
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Cycle Proteins - genetics; Congenital diseases; Consanguinity; DNA, Mitochondrial - genetics; Enzymes; Exons; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Genetic Predisposition to Disease; Genetic research; Genetics of eukaryotes. Biological and molecular evolution; Homozygote; Humans; Infant, Newborn; Male; Medical genetics; Medical sciences; Mitochondria; Mitochondria - genetics; Mitochondrial Encephalomyopathies - genetics; Mitochondrial Encephalomyopathies - metabolism; Mitochondrial Proteins - genetics; Molecular and cellular biology; Mutation; Protein Biosynthesis; Protein synthesis; Proteins; RNA Splice Sites - genetics; RNA Splicing - genetics; RNA, Messenger - genetics
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2012.08.019

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.