A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension

Hui Lin Chin; Denise Li Meng Goh; Furene Sijia Wang; Stacey Kiat Hong Tay; Chew Kiat Heng; Claudia Donnini; Enrico Baruffini; Ophry Pines

doi:10.1007/s00109-019-01834-5

A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension

Hui Lin Chin^*, Denise Li Meng Goh, Furene Sijia Wang, Stacey Kiat Hong Tay, Chew Kiat Heng, Claudia Donnini, Enrico Baruffini, Ophry Pines

^*Corresponding author for this work

Department of Microbiology and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Abstract: The VARS2 gene encodes a mitochondrial valyl-transfer RNA synthetase which is used in mitochondrial translation. To date, several patients with VARS2 pathogenic variants have been described in the literature. These patients have features of lactic acidosis with encephalomyopathy. We present a case of an infant with lactic acidosis, failure to thrive, and severe primary pulmonary hypertension who was found to be a compound heterozygote for two novel VARS2 variants (c.1940C>T, p.(Thr647Met) and c.2318G>A, p.(Arg773Gln)). The patient was treated with vitamin supplements and a carbohydrate-restricted diet. The lactic acidosis and failure to thrive resolved, and he showed good growth and development. Functional studies and molecular analysis employed a yeast model system and the VAS1 gene (yeast homolog of VARS2). VAS1 genes harboring either one of two mutations corresponding to the two novel variants in the VARS2 gene, exhibited partially reduced function in haploid yeast strains. A combination of both VAS1 variant alleles in a diploid yeast cell exhibited a more significant decrease in oxidative metabolism-dependent growth and in the oxygen consumption rate (reminiscent of the patient who carries two mutant VARS2 alleles). Our results demonstrate the pathogenicity of the biallellic novel VARS2 variants. Key messages: • A case of an infant who is a compound heterozygote for two novel VARS2 variants. • This infant displayed lactic acidosis, failure to thrive, and pulmonary hypertension. • Treatment of the patient with a carbohydrate-restricted diet resulted in good growth and development. • Studies with the homologous yeast VAS1 gene showed reduced function of corresponding single mutant in haploid yeast strains. • A combination of both VAS1 variant alleles in diploid yeast exhibited a more significant decrease in function, thereby confirming the pathogenicity of the biallellic novel VARS2 variants.

Original language	American English
Pages (from-to)	1557-1566
Number of pages	10
Journal	Journal of Molecular Medicine
Volume	97
Issue number	11
DOIs	https://doi.org/10.1007/s00109-019-01834-5
State	Published - 1 Nov 2019

Bibliographical note

Funding Information:
This study was supported, in part, by a MMID-2 SHARE grant, CREATE, National Research Foundation (NRF) of Singapore to OP, HLC, and CKH; Telethon GGP15041 to CD and EB and DIP; ISF, Pakula family grants to OP.

Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Keywords

Aminoacyl-tRNA synthetase
Failure to thrive
Mitochondrial disorder
OXPHOS defect
Pulmonary hypertension
VARS2
VAS1
Yeast model system

Access to Document

10.1007/s00109-019-01834-5

Cite this

@article{ceab8c0283a04c93b2f55af8461acf47,

title = "A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension",

abstract = "Abstract: The VARS2 gene encodes a mitochondrial valyl-transfer RNA synthetase which is used in mitochondrial translation. To date, several patients with VARS2 pathogenic variants have been described in the literature. These patients have features of lactic acidosis with encephalomyopathy. We present a case of an infant with lactic acidosis, failure to thrive, and severe primary pulmonary hypertension who was found to be a compound heterozygote for two novel VARS2 variants (c.1940C>T, p.(Thr647Met) and c.2318G>A, p.(Arg773Gln)). The patient was treated with vitamin supplements and a carbohydrate-restricted diet. The lactic acidosis and failure to thrive resolved, and he showed good growth and development. Functional studies and molecular analysis employed a yeast model system and the VAS1 gene (yeast homolog of VARS2). VAS1 genes harboring either one of two mutations corresponding to the two novel variants in the VARS2 gene, exhibited partially reduced function in haploid yeast strains. A combination of both VAS1 variant alleles in a diploid yeast cell exhibited a more significant decrease in oxidative metabolism-dependent growth and in the oxygen consumption rate (reminiscent of the patient who carries two mutant VARS2 alleles). Our results demonstrate the pathogenicity of the biallellic novel VARS2 variants. Key messages: • A case of an infant who is a compound heterozygote for two novel VARS2 variants. • This infant displayed lactic acidosis, failure to thrive, and pulmonary hypertension. • Treatment of the patient with a carbohydrate-restricted diet resulted in good growth and development. • Studies with the homologous yeast VAS1 gene showed reduced function of corresponding single mutant in haploid yeast strains. • A combination of both VAS1 variant alleles in diploid yeast exhibited a more significant decrease in function, thereby confirming the pathogenicity of the biallellic novel VARS2 variants.",

keywords = "Aminoacyl-tRNA synthetase, Failure to thrive, Mitochondrial disorder, OXPHOS defect, Pulmonary hypertension, VARS2, VAS1, Yeast model system",

author = "Chin, {Hui Lin} and Goh, {Denise Li Meng} and Wang, {Furene Sijia} and Tay, {Stacey Kiat Hong} and Heng, {Chew Kiat} and Claudia Donnini and Enrico Baruffini and Ophry Pines",

note = "Funding Information: This study was supported, in part, by a MMID-2 SHARE grant, CREATE, National Research Foundation (NRF) of Singapore to OP, HLC, and CKH; Telethon GGP15041 to CD and EB and DIP; ISF, Pakula family grants to OP. Publisher Copyright: {\textcopyright} 2019, Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2019",

month = nov,

day = "1",

doi = "10.1007/s00109-019-01834-5",

language = "American English",

volume = "97",

pages = "1557--1566",

journal = "Journal of Molecular Medicine",

issn = "0946-2716",

publisher = "Springer Verlag",

number = "11",

}

TY - JOUR

T1 - A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension

AU - Chin, Hui Lin

AU - Goh, Denise Li Meng

AU - Wang, Furene Sijia

AU - Tay, Stacey Kiat Hong

AU - Heng, Chew Kiat

AU - Donnini, Claudia

AU - Baruffini, Enrico

AU - Pines, Ophry

N1 - Funding Information: This study was supported, in part, by a MMID-2 SHARE grant, CREATE, National Research Foundation (NRF) of Singapore to OP, HLC, and CKH; Telethon GGP15041 to CD and EB and DIP; ISF, Pakula family grants to OP. Publisher Copyright: © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Abstract: The VARS2 gene encodes a mitochondrial valyl-transfer RNA synthetase which is used in mitochondrial translation. To date, several patients with VARS2 pathogenic variants have been described in the literature. These patients have features of lactic acidosis with encephalomyopathy. We present a case of an infant with lactic acidosis, failure to thrive, and severe primary pulmonary hypertension who was found to be a compound heterozygote for two novel VARS2 variants (c.1940C>T, p.(Thr647Met) and c.2318G>A, p.(Arg773Gln)). The patient was treated with vitamin supplements and a carbohydrate-restricted diet. The lactic acidosis and failure to thrive resolved, and he showed good growth and development. Functional studies and molecular analysis employed a yeast model system and the VAS1 gene (yeast homolog of VARS2). VAS1 genes harboring either one of two mutations corresponding to the two novel variants in the VARS2 gene, exhibited partially reduced function in haploid yeast strains. A combination of both VAS1 variant alleles in a diploid yeast cell exhibited a more significant decrease in oxidative metabolism-dependent growth and in the oxygen consumption rate (reminiscent of the patient who carries two mutant VARS2 alleles). Our results demonstrate the pathogenicity of the biallellic novel VARS2 variants. Key messages: • A case of an infant who is a compound heterozygote for two novel VARS2 variants. • This infant displayed lactic acidosis, failure to thrive, and pulmonary hypertension. • Treatment of the patient with a carbohydrate-restricted diet resulted in good growth and development. • Studies with the homologous yeast VAS1 gene showed reduced function of corresponding single mutant in haploid yeast strains. • A combination of both VAS1 variant alleles in diploid yeast exhibited a more significant decrease in function, thereby confirming the pathogenicity of the biallellic novel VARS2 variants.

AB - Abstract: The VARS2 gene encodes a mitochondrial valyl-transfer RNA synthetase which is used in mitochondrial translation. To date, several patients with VARS2 pathogenic variants have been described in the literature. These patients have features of lactic acidosis with encephalomyopathy. We present a case of an infant with lactic acidosis, failure to thrive, and severe primary pulmonary hypertension who was found to be a compound heterozygote for two novel VARS2 variants (c.1940C>T, p.(Thr647Met) and c.2318G>A, p.(Arg773Gln)). The patient was treated with vitamin supplements and a carbohydrate-restricted diet. The lactic acidosis and failure to thrive resolved, and he showed good growth and development. Functional studies and molecular analysis employed a yeast model system and the VAS1 gene (yeast homolog of VARS2). VAS1 genes harboring either one of two mutations corresponding to the two novel variants in the VARS2 gene, exhibited partially reduced function in haploid yeast strains. A combination of both VAS1 variant alleles in a diploid yeast cell exhibited a more significant decrease in oxidative metabolism-dependent growth and in the oxygen consumption rate (reminiscent of the patient who carries two mutant VARS2 alleles). Our results demonstrate the pathogenicity of the biallellic novel VARS2 variants. Key messages: • A case of an infant who is a compound heterozygote for two novel VARS2 variants. • This infant displayed lactic acidosis, failure to thrive, and pulmonary hypertension. • Treatment of the patient with a carbohydrate-restricted diet resulted in good growth and development. • Studies with the homologous yeast VAS1 gene showed reduced function of corresponding single mutant in haploid yeast strains. • A combination of both VAS1 variant alleles in diploid yeast exhibited a more significant decrease in function, thereby confirming the pathogenicity of the biallellic novel VARS2 variants.

KW - Aminoacyl-tRNA synthetase

KW - Failure to thrive

KW - Mitochondrial disorder

KW - OXPHOS defect

KW - Pulmonary hypertension

KW - VARS2

KW - VAS1

KW - Yeast model system

UR - http://www.scopus.com/inward/record.url?scp=85073810546&partnerID=8YFLogxK

U2 - 10.1007/s00109-019-01834-5

DO - 10.1007/s00109-019-01834-5

M3 - Article

C2 - 31529142

AN - SCOPUS:85073810546

SN - 0946-2716

VL - 97

SP - 1557

EP - 1566

JO - Journal of Molecular Medicine

JF - Journal of Molecular Medicine

IS - 11

ER -

A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this