title: Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit.
abstract: The mitochondrial inner membrane possesses distinct subdomains including cristae, which are lamellar structures invaginated into the mitochondrial matrix and contain the respiratory complexes. Generation of inner membrane domains requires the complex interplay between the respiratory complexes, mitochondrial lipids and the recently identified mitochondrial contact site and cristae organizing system (MICOS) complex. Proper organization of the mitochondrial inner membrane has recently been shown to be important for respiratory function in yeast. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with a neurodegenerative disorder accompanied by hyperlactatemia, 3-methylglutaconic aciduria, disturbed hepatocellular function with abnormal cristae morphology in liver and cerebellar and vermis atrophy, which suggest mitochondrial dysfunction. Using homozygosity mapping and exome sequencing the patients were found to be homozygous for the p.(Gly15Glufs*75) variant in the QIL1/MIC13 (C19orf70) gene. QIL1/MIC13 is a constituent of MICOS, a six subunit complex that helps to form and/or stabilize cristae junctions and determine the placement, distribution and number of cristae within mitochondria. In patient fibroblasts both MICOS subunits QIL1/MIC13 and MIC10 were absent whereas MIC60 was present in a comparable abundance to that of the control. We conclude that QIL1/MIC13 deficiency in human, is associated with disassembly of the MICOS complex, with the associated aberration of cristae morphology and mitochondrial respiratory dysfunction. 3-Methylglutaconic aciduria is associated with variants in genes encoding mitochondrial inner membrane organizing determinants, including TAZ, DNAJC19, SERAC1 and QIL1/MIC13.
authors.affiliation: Department of Day Hospitalization, Schneider Children's Medical Center of Israel, Petah Tiqva, and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Zeharia
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, CA, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Friedman
authors.affiliation: Department of Pathology, Rabin Medical Center, Beilinson Campus, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ana
authors.initials: A
authors.lastname: Tobar
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, the Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.affiliation: Imaging Department, Schneider Children's Medical Center of Israel, Petah Tiqva, and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Osnat
authors.initials: O
authors.lastname: Konen
authors.affiliation: Department of Pathology, Hadassah, the Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yacov
authors.initials: Y
authors.lastname: Fellig
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, the Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, CA, USA.
authors.forename: Jodi
authors.initials: J
authors.lastname: Nunnari
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, the Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics*; D002478:Cells, Cultured; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D008107:Liver Diseases / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D016366:Open Reading Frames; D013577:Syndrome
chemical_list: D024101:Mitochondrial Proteins