MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.
We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain (MRC) activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype.
Department of Life Sciences, University of Parma, Parma, Italy.
Enrico
E
Baruffini
Cristina
C
Dallabona
Federica
F
Invernizzi
John W
JW
Yarham
Laura
L
Melchionda
Emma L
EL
Blakely
Eleonora
E
Lamantea
Claudia
C
Donnini
Saikat
S
Santra
Suresh
S
Vijayaraghavan
Helen P
HP
Roper
Alberto
A
Burlina
Robert
R
Kopajtich
Anett
A
Walther
Tim M
TM
Strom
Tobias B
TB
Haack
Holger
H
Prokisch
Robert W
RW
Taylor
Ileana
I
Ferrero
Massimo
M
Zeviani
Daniele
D
Ghezzi
D000140:Acidosis, Lactic / Q000235:genetics*; D000293:Adolescent; D017668:Age of Onset; D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D045222:Electron Transport Chain Complex Proteins / Q000172:deficiency*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D016601:RNA-Binding Proteins; D016415:Sequence Alignment; D015003:Yeasts / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D002352:Carrier Proteins; D045222:Electron Transport Chain Complex Proteins; C492006:MTO1 protein, human; D016601:RNA-Binding Proteins
MTO1; hypertrophic cardiomyopathy; lactic acidosis; mitochondrial disorder; yeast