Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy

Alexandra Götz, Henna Tyynismaa, Liliya Euro, Pekka Ellonen, Tuulia Hyötyläinen, Tiina Ojala, Riikka H. Hämäläinen, Johanna Tommiska, Taneli Raivio, Matej Orešič, Riitta Karikoski, Outi Tammela, Kalle O. J. Simola, Anders Paetau, Tiina Tyni, Anu Suomalainen (Corresponding Author)

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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.
Original languageEnglish
Pages (from-to)635-642
JournalAmerican Journal of Human Genetics
Volume88
Issue number5
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

Fingerprint

Alanine-tRNA Ligase
Exome
Cardiomyopathies
Mutation
Transfer RNA Aminoacylation
Mitochondrial Diseases
Hypertrophic Cardiomyopathy
Missense Mutation
Cytochrome-c Oxidase Deficiency
Electron Transport Complex I
Organ Specificity
Electron Transport
Transfer RNA
Genes
Organism Cloning
Siblings
Heart Failure

Cite this

Götz, Alexandra ; Tyynismaa, Henna ; Euro, Liliya ; Ellonen, Pekka ; Hyötyläinen, Tuulia ; Ojala, Tiina ; Hämäläinen, Riikka H. ; Tommiska, Johanna ; Raivio, Taneli ; Orešič, Matej ; Karikoski, Riitta ; Tammela, Outi ; Simola, Kalle O. J. ; Paetau, Anders ; Tyni, Tiina ; Suomalainen, Anu. / Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. In: American Journal of Human Genetics. 2011 ; Vol. 88, No. 5. pp. 635-642.
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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.",
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Götz, A, Tyynismaa, H, Euro, L, Ellonen, P, Hyötyläinen, T, Ojala, T, Hämäläinen, RH, Tommiska, J, Raivio, T, Orešič, M, Karikoski, R, Tammela, O, Simola, KOJ, Paetau, A, Tyni, T & Suomalainen, A 2011, 'Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy', American Journal of Human Genetics, vol. 88, no. 5, pp. 635-642. https://doi.org/10.1016/j.ajhg.2011.04.006

Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. / Götz, Alexandra; Tyynismaa, Henna; Euro, Liliya; Ellonen, Pekka; Hyötyläinen, Tuulia; Ojala, Tiina; Hämäläinen, Riikka H.; Tommiska, Johanna; Raivio, Taneli; Orešič, Matej; Karikoski, Riitta; Tammela, Outi; Simola, Kalle O. J.; Paetau, Anders; Tyni, Tiina; Suomalainen, Anu (Corresponding Author).

In: American Journal of Human Genetics, Vol. 88, No. 5, 2011, p. 635-642.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy

AU - Götz, Alexandra

AU - Tyynismaa, Henna

AU - Euro, Liliya

AU - Ellonen, Pekka

AU - Hyötyläinen, Tuulia

AU - Ojala, Tiina

AU - Hämäläinen, Riikka H.

AU - Tommiska, Johanna

AU - Raivio, Taneli

AU - Orešič, Matej

AU - Karikoski, Riitta

AU - Tammela, Outi

AU - Simola, Kalle O. J.

AU - Paetau, Anders

AU - Tyni, Tiina

AU - Suomalainen, Anu

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2011.04.006

DO - 10.1016/j.ajhg.2011.04.006

M3 - Article

VL - 88

SP - 635

EP - 642

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -