Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy

Jennifer Friedman,John R Crawford,Geneviève Bernard,Marisa I Mendes,Luan T Tran,Tawfeg Ben‐Omran ,David Dimmock,Kristen Wigby,Stephen F Kingsmore,Amber Hildreth,Rengang Wang,Alanna E Koehler,Damir Musaev,Gajja S Salomons,Woo-Kuen Lo ,Andrea Accogli,Lu Zhai ,Maha S Zaki,Valentina Stanley,Tarek Omar ,Shimul Chowdhury,Kiely N James,Desirée E.c Smith ,Meredith S Wright,Shareef Nahas,Kether Guerrero,Zhiwen Xu,Mahmoud Y Issa,Joseph G Gleeson

doi:10.1038/s41467-018-07067-3

Abstract

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.

Highlights

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation
Mutations in 31 different ARS genes are currently implicated in recessive diseases, with mutations in most mitochondriallocalized ARS genes associated with mitochondrial encephalopathies, and cytoplasmic-localized ARS genes associated with a wider range of diseases but affecting primarily the nervous system
The researchers enrolling subjects from these three locations were matched through collaborative networks and the Matchmaker Exchange[1] and recognized a common core phenotype of neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA), which contributed to the OMIM entry #617802 linked to VARS

Summary

Introduction

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. The spectrum of genes responsible for pediatric neurodevelopmental and neurodegenerative conditions (PNDDC) is extraordinarily broad, often requiring a whole-exome or whole-genome sequencing approach rather than a targeted gene or panel approach in order to achieve a molecular diagnosis and to identify new causes of disease. This is in part due to the vast number of genetic forms of PNDDC, in addition to wide-ranging phenotypic and genetic heterogeneity among these conditions. They reported two pathogenic variants NM_006295.2: c.2653C>T p.(Leu885Phe) and NM_006295.2:c.3173G>A p. (Arg1058Gln) in two consanguineous families with epileptic encephalopathy; phenotypic spectrum and function were not studied[3]

Methods

Results

Conclusion