title: RMND1 deficiency associated with neonatal lactic acidosis, infantile onset renal failure, deafness, and multiorgan involvement.
abstract: RMND1 is an integral inner membrane mitochondrial protein that assembles into a large 240 kDa complex to support translation of the 13 polypeptides encoded on mtDNA, all of which are essential subunits of the oxidative phosphorylation (OXPHOS) complexes. Variants in RMND1 produce global defects in mitochondrial translation and were first reported in patients with severe neurological phenotypes leading to mortality in the first months of life. Using whole-exome sequencing, we identified compound heterozygous RMND1 variants in a 4-year-old patient with congenital lactic acidosis, severe myopathy, hearing loss, renal failure, and dysautonomia. The levels of mitochondrial ribosome proteins were reduced in patient fibroblasts, causing a translation defect, which was rescued by expression of the wild-type cDNA. RMND1 was almost undetectable by immunoblot analysis in patient muscle and fibroblasts. BN-PAGE analysis showed a severe combined OXPHOS assembly defect that was more prominent in patient muscle than in fibroblasts. Immunofluorescence experiments showed that RMND1 localizes to discrete foci in the mitochondrial network, juxtaposed to RNA granules where the primary mitochondrial transcripts are processed. RMND1 foci were not detected in patient fibroblasts. We hypothesize that RMND1 acts to anchor or stabilize the mitochondrial ribosome near the sites where the mRNAs are matured, spatially coupling post-transcriptional handling mRNAs with their translation, and that loss of function variants in RMND1 are associated with a unique constellation of clinical phenotypes that vary with the severity of the mitochondrial translation defect.
authors.affiliation: Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Janer
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.|Treatable Intellectual Disability Endeavour in British Columbia, Vancouver BC, Canada.|Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Department of Medical Genetics, BC Children's and Women's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Clara Dm
authors.initials: CD
authors.lastname: van Karnebeek
authors.affiliation: Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Florin
authors.initials: F
authors.lastname: Sasarman
authors.affiliation: Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Hana
authors.initials: H
authors.lastname: Antonicka
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Malak
authors.initials: M
authors.lastname: Al Ghamdi
authors.affiliation: Treatable Intellectual Disability Endeavour in British Columbia, Vancouver BC, Canada.|Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Department of Medical Genetics, BC Children's and Women's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Casper
authors.initials: C
authors.lastname: Shyr
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Pediatrics, BC Children's and Women's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Mary
authors.initials: M
authors.lastname: Dunbar
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.|Treatable Intellectual Disability Endeavour in British Columbia, Vancouver BC, Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler-Ispiroglu
authors.affiliation: Treatable Intellectual Disability Endeavour in British Columbia, Vancouver BC, Canada.|Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Department of Medical Genetics, BC Children's and Women's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Treatable Intellectual Disability Endeavour in British Columbia, Vancouver BC, Canada.|Department of Pathology and Laboratory Medicine, Department of Pediatrics, BC Children's and Women's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Hilary
authors.initials: H
authors.lastname: Vallance
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Janis
authors.initials: J
authors.lastname: Dionne
authors.affiliation: Treatable Intellectual Disability Endeavour in British Columbia, Vancouver BC, Canada.|Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Department of Medical Genetics, BC Children's and Women's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.affiliation: Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000235:genetics*; D002675:Child, Preschool; D003638:Deafness / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure / Q000235:genetics*; D051437:Renal Insufficiency / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C578871:RMND1 protein, human