title: Toward genotype phenotype correlations in GFM1 mutations.
abstract: Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases. We report two novel GFM1 mutations in two unrelated patients with encephalopathy and liver failure respectively. The first patient had intrauterine growth retardation, seizures, encephalopathy and developmental delay. Brain MRI showed hypoplasia of the vermis and severe pontine atrophy of the brainstem that were similar to those reported in patients with mitochondrial translation deficiencies. The second patient had liver failure with hypoglycemia. Respiratory chain analysis showed a complex IV deficiency in muscle of both patients. A 10K SNP genotyping detected several regions of homozygosity in the two patients. In vitro translation deficiency prompted us to study genes involved in mitochondrial translation. Therefore, we sequenced the GFM1 gene, encoding the mitochondrial translation factor EFG1, included in a shared homozygous region and identified two different homozygous mutations (R671C and L398P). Modeling studies of EFG1 protein suggested that the R671C mutation disrupts an inter-subunit interface and could locally destabilize the mutant protein. The second mutation (L398P) disrupted the H-bond network in a rich-beta-sheet domain, and may have a dramatic effect on local structure. GFM1 mutations have been seldom reported and are associated with different clinical presentation. By modeling the structure of the protein and the position of the various mutations we suggest that the clinical phenotypes of the patients could be related to the localization of the mutations.
authors: Department of Genetics, Hôpital Necker-Enfants Malades, Université Paris Descartes and INSERM U781, 149 rue de Sèvres, 75015 Paris, France.
authors: Louise
authors: L
authors: Galmiche
authors: Valérie
authors: V
authors: Serre
authors: Marine
authors: M
authors: Beinat
authors: Raïssa
authors: R
authors: Zossou
authors: Zahra
authors: Z
authors: Assouline
authors: Anne-Sophie
authors: AS
authors: Lebre
authors: Florence
authors: F
authors: Chretien
authors: Ruthie
authors: R
authors: Shenhav
authors: Avraham
authors: A
authors: Zeharia
authors: Ann
authors: A
authors: Saada
authors: Vanessa
authors: V
authors: Vedrenne
authors: Nathalie
authors: N
authors: Boddaert
authors: Pascale
authors: P
authors: de Lonlay
authors: Marlène
authors: M
authors: Rio
authors: Arnold
authors: A
authors: Munnich
authors: Agnès
authors: A
authors: Rötig
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D001925:Brain Damage, Chronic / Q000235:genetics / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D017093:Liver Failure / Q000235:genetics / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D020653:Peptide Elongation Factor G / Q000235:genetics* / Q000378:metabolism*; D011247:Pregnancy; D011859:Radiography; D017422:Sequence Analysis, DNA
chemical_list: C441680:GFM1 protein, human; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D020653:Peptide Elongation Factor G