title: Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy.
abstract: Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Götz
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
authors.forename: Liliya
authors.initials: L
authors.lastname: Euro
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.forename: Tuulia
authors.initials: T
authors.lastname: Hyötyläinen
authors.forename: Tiina
authors.initials: T
authors.lastname: Ojala
authors.forename: Riikka H
authors.initials: RH
authors.lastname: Hämäläinen
authors.forename: Johanna
authors.initials: J
authors.lastname: Tommiska
authors.forename: Taneli
authors.initials: T
authors.lastname: Raivio
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.forename: Riitta
authors.initials: R
authors.lastname: Karikoski
authors.forename: Outi
authors.initials: O
authors.lastname: Tammela
authors.forename: Kalle O J
authors.initials: KO
authors.lastname: Simola
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Tiina
authors.initials: T
authors.lastname: Tyni
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000412:Alanine-tRNA Ligase / Q000235:genetics*; D020029:Base Pairing; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary
chemical_list: D004272:DNA, Mitochondrial; D000412:Alanine-tRNA Ligase