title: Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency.
abstract: We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site. Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency.
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA; Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA.
authors.forename: Mariella T
authors.initials: MT
authors.lastname: Simon
authors.affiliation: Human Genetics Program, Sanford Children's Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA.
authors.forename: Bobby G
authors.initials: BG
authors.lastname: Ng
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Friederich
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA; Department of Pediatrics, University of California Irvine, Irvine, CA, USA.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Wang
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Boyer
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Kircher
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Collard
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA, USA.
authors.forename: Kati J
authors.initials: KJ
authors.lastname: Buckingham
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA; Department of Pediatrics, University of California Irvine, Irvine, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Chang
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
authors.forename: Johan L K
authors.initials: JLK
authors.lastname: Van Hove
authors.affiliation: Human Genetics Program, Sanford Children's Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA.
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA; Department of Pediatrics, University of California Irvine, Irvine, CA, USA. Electronic address: jabdenur@choc.org.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Abdenur
mesh_terms: D002648:Child; D002675:Child, Preschool; D000013:Congenital Abnormalities / Q000235:genetics* / Q000473:pathology*; D015870:Gene Expression; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics*; D010085:Oxidative Phosphorylation; D020653:Peptide Elongation Factor G / Q000096:biosynthesis* / Q000235:genetics*; D022821:RNA Splice Sites
chemical_list: C441680:GFM1 protein, human; D024101:Mitochondrial Proteins; D020653:Peptide Elongation Factor G; D022821:RNA Splice Sites
keywords: Congenital disorders of glycosylation; Cryptic splice site; GFM1; Mitochondrial disease; Mitochondrial elongation factor