Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy

Jenni M Elo; Srujana S Yadavalli; Liliya Euro; Pirjo Isohanni; Alexandra Götz; Christopher J Carroll; Leena Valanne; Fowzan S Alkuraya; Johanna Uusimaa; Anders Paetau; Eric M Caruso; Helena Pihko; Michael Ibba; Henna Tyynismaa; Anu Suomalainen

doi:10.1093/hmg/dds294

Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy

Jenni M Elo, Srujana S Yadavalli, Liliya Euro, Pirjo Isohanni, Alexandra Götz, Christopher J Carroll, Leena Valanne, Fowzan S Alkuraya, Johanna Uusimaa, Anders Paetau, Eric M Caruso, Helena Pihko, Michael Ibba, Henna Tyynismaa, Anu Suomalainen

Transcription, RNA, and Gene Medicine Program

115 Citationer (Scopus)

Abstract

Next-generation sequencing has turned out to be a powerful tool to uncover genetic basis of childhood mitochondrial disorders. We utilized whole-exome analysis and discovered novel compound heterozygous mutations in FARS2 (mitochondrial phenylalanyl transfer RNA synthetase), encoding the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) in two patients with fatal epileptic mitochondrial encephalopathy. The mutations affected highly conserved amino acids, p.I329T and p.D391V. Recently, a homozygous FARS2 variant p.Y144C was reported in a Saudi girl with mitochondrial encephalopathy, but the pathogenic role of the variant remained open. Clinical features, including postnatal onset, catastrophic epilepsy, lactic acidemia, early lethality and neuroimaging findings of the patients with FARS2 variants, resembled each other closely, and neuropathology was consistent with Alpers syndrome. Our structural analysis of mtPheRS predicted that p.I329T weakened ATP binding in the aminoacylation domain, and in vitro studies with recombinant mutant protein showed decreased affinity of this variant to ATP. Furthermore, p.D391V and p.Y144C were predicted to disrupt synthetase function by interrupting the rotation of the tRNA anticodon stem-binding domain from a closed to an open form. In vitro characterization indicated reduced affinity of p.D391V mutant protein to phenylalanine, whereas p.Y144C disrupted tRNA binding. The stability of p.I329T and p.D391V mutants in a refolding assay was impaired. Our results imply that the three FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. This study establishes a new genetic cause of infantile mitochondrial Alpers encephalopathy and reports a new mitochondrial aminoacyl-tRNA synthetase as a cause of mitochondrial disease.

Originalsprog	Engelsk
Tidsskrift	Human Molecular Genetics
Vol/bind	21
Udgave nummer	20
Sider (fra-til)	4521-9
Antal sider	9
ISSN	0964-6906
DOI	https://doi.org/10.1093/hmg/dds294
Status	Udgivet - 15 okt. 2012

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10.1093/hmg/dds294

https://academic.oup.com/hmg/article-pdf/21/20/4521/17257079/dds294.pdf

Citationsformater

Elo, J. M., Yadavalli, S. S., Euro, L., Isohanni, P., Götz, A., Carroll, C. J., Valanne, L., Alkuraya, F. S., Uusimaa, J., Paetau, A., Caruso, E. M., Pihko, H., Ibba, M., Tyynismaa, H., & Suomalainen, A. (2012). Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. Human Molecular Genetics, 21(20), 4521-9. https://doi.org/10.1093/hmg/dds294

Elo, JM, Yadavalli, SS, Euro, L, Isohanni, P, Götz, A, Carroll, CJ, Valanne, L, Alkuraya, FS, Uusimaa, J, Paetau, A, Caruso, EM, Pihko, H, Ibba, M, Tyynismaa, H & Suomalainen, A 2012, 'Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy', Human Molecular Genetics, bind 21, nr. 20, s. 4521-9. https://doi.org/10.1093/hmg/dds294

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title = "Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy",

abstract = "Next-generation sequencing has turned out to be a powerful tool to uncover genetic basis of childhood mitochondrial disorders. We utilized whole-exome analysis and discovered novel compound heterozygous mutations in FARS2 (mitochondrial phenylalanyl transfer RNA synthetase), encoding the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) in two patients with fatal epileptic mitochondrial encephalopathy. The mutations affected highly conserved amino acids, p.I329T and p.D391V. Recently, a homozygous FARS2 variant p.Y144C was reported in a Saudi girl with mitochondrial encephalopathy, but the pathogenic role of the variant remained open. Clinical features, including postnatal onset, catastrophic epilepsy, lactic acidemia, early lethality and neuroimaging findings of the patients with FARS2 variants, resembled each other closely, and neuropathology was consistent with Alpers syndrome. Our structural analysis of mtPheRS predicted that p.I329T weakened ATP binding in the aminoacylation domain, and in vitro studies with recombinant mutant protein showed decreased affinity of this variant to ATP. Furthermore, p.D391V and p.Y144C were predicted to disrupt synthetase function by interrupting the rotation of the tRNA anticodon stem-binding domain from a closed to an open form. In vitro characterization indicated reduced affinity of p.D391V mutant protein to phenylalanine, whereas p.Y144C disrupted tRNA binding. The stability of p.I329T and p.D391V mutants in a refolding assay was impaired. Our results imply that the three FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. This study establishes a new genetic cause of infantile mitochondrial Alpers encephalopathy and reports a new mitochondrial aminoacyl-tRNA synthetase as a cause of mitochondrial disease.",

keywords = "Amino Acid Sequence, Anticodon, Base Sequence, Diffuse Cerebral Sclerosis of Schilder, Exome, Female, Humans, Infant, Mitochondria, Mitochondrial Diseases, Molecular Sequence Data, Mutation, Phenylalanine-tRNA Ligase, Protein Folding, RNA, Transfer",

author = "Elo, {Jenni M} and Yadavalli, {Srujana S} and Liliya Euro and Pirjo Isohanni and Alexandra G{\"o}tz and Carroll, {Christopher J} and Leena Valanne and Alkuraya, {Fowzan S} and Johanna Uusimaa and Anders Paetau and Caruso, {Eric M} and Helena Pihko and Michael Ibba and Henna Tyynismaa and Anu Suomalainen",

year = "2012",

month = oct,

day = "15",

doi = "10.1093/hmg/dds294",

language = "English",

volume = "21",

pages = "4521--9",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "20",

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TY - JOUR

T1 - Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy

AU - Elo, Jenni M

AU - Yadavalli, Srujana S

AU - Euro, Liliya

AU - Isohanni, Pirjo

AU - Götz, Alexandra

AU - Carroll, Christopher J

AU - Valanne, Leena

AU - Alkuraya, Fowzan S

AU - Uusimaa, Johanna

AU - Paetau, Anders

AU - Caruso, Eric M

AU - Pihko, Helena

AU - Ibba, Michael

AU - Tyynismaa, Henna

AU - Suomalainen, Anu

PY - 2012/10/15

Y1 - 2012/10/15

N2 - Next-generation sequencing has turned out to be a powerful tool to uncover genetic basis of childhood mitochondrial disorders. We utilized whole-exome analysis and discovered novel compound heterozygous mutations in FARS2 (mitochondrial phenylalanyl transfer RNA synthetase), encoding the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) in two patients with fatal epileptic mitochondrial encephalopathy. The mutations affected highly conserved amino acids, p.I329T and p.D391V. Recently, a homozygous FARS2 variant p.Y144C was reported in a Saudi girl with mitochondrial encephalopathy, but the pathogenic role of the variant remained open. Clinical features, including postnatal onset, catastrophic epilepsy, lactic acidemia, early lethality and neuroimaging findings of the patients with FARS2 variants, resembled each other closely, and neuropathology was consistent with Alpers syndrome. Our structural analysis of mtPheRS predicted that p.I329T weakened ATP binding in the aminoacylation domain, and in vitro studies with recombinant mutant protein showed decreased affinity of this variant to ATP. Furthermore, p.D391V and p.Y144C were predicted to disrupt synthetase function by interrupting the rotation of the tRNA anticodon stem-binding domain from a closed to an open form. In vitro characterization indicated reduced affinity of p.D391V mutant protein to phenylalanine, whereas p.Y144C disrupted tRNA binding. The stability of p.I329T and p.D391V mutants in a refolding assay was impaired. Our results imply that the three FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. This study establishes a new genetic cause of infantile mitochondrial Alpers encephalopathy and reports a new mitochondrial aminoacyl-tRNA synthetase as a cause of mitochondrial disease.

AB - Next-generation sequencing has turned out to be a powerful tool to uncover genetic basis of childhood mitochondrial disorders. We utilized whole-exome analysis and discovered novel compound heterozygous mutations in FARS2 (mitochondrial phenylalanyl transfer RNA synthetase), encoding the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) in two patients with fatal epileptic mitochondrial encephalopathy. The mutations affected highly conserved amino acids, p.I329T and p.D391V. Recently, a homozygous FARS2 variant p.Y144C was reported in a Saudi girl with mitochondrial encephalopathy, but the pathogenic role of the variant remained open. Clinical features, including postnatal onset, catastrophic epilepsy, lactic acidemia, early lethality and neuroimaging findings of the patients with FARS2 variants, resembled each other closely, and neuropathology was consistent with Alpers syndrome. Our structural analysis of mtPheRS predicted that p.I329T weakened ATP binding in the aminoacylation domain, and in vitro studies with recombinant mutant protein showed decreased affinity of this variant to ATP. Furthermore, p.D391V and p.Y144C were predicted to disrupt synthetase function by interrupting the rotation of the tRNA anticodon stem-binding domain from a closed to an open form. In vitro characterization indicated reduced affinity of p.D391V mutant protein to phenylalanine, whereas p.Y144C disrupted tRNA binding. The stability of p.I329T and p.D391V mutants in a refolding assay was impaired. Our results imply that the three FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. This study establishes a new genetic cause of infantile mitochondrial Alpers encephalopathy and reports a new mitochondrial aminoacyl-tRNA synthetase as a cause of mitochondrial disease.

KW - Amino Acid Sequence

KW - Anticodon

KW - Base Sequence

KW - Diffuse Cerebral Sclerosis of Schilder

KW - Exome

KW - Female

KW - Humans

KW - Infant

KW - Mitochondria

KW - Mitochondrial Diseases

KW - Molecular Sequence Data

KW - Mutation

KW - Phenylalanine-tRNA Ligase

KW - Protein Folding

KW - RNA, Transfer

U2 - 10.1093/hmg/dds294

DO - 10.1093/hmg/dds294

M3 - Journal article

C2 - 22833457

SN - 0964-6906

VL - 21

SP - 4521

EP - 4529

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 20

ER -

Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy

Abstract

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