Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies

Xingao Wang; Qun Wang; Hefei Tang; Bin Chen; Xiang Dong; Songtao Niu; Shaowu Li; Yuzhi Shi; Wei Shan; Zaiqiang Zhang

doi:10.3389/fneur.2019.01321

Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies

Front Neurol. 2019 Dec 17:10:1321. doi: 10.3389/fneur.2019.01321. eCollection 2019.

Authors

Xingao Wang^{1

2}, Qun Wang^{1

2

3

4}, Hefei Tang^{1

2}, Bin Chen^{1

2}, Xiang Dong⁵, Songtao Niu^{1

2}, Shaowu Li⁶, Yuzhi Shi^{1

2}, Wei Shan^{1

2

3

4}, Zaiqiang Zhang^{1

2}

Affiliations

¹ Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
² China National Clinical Research Center for Neurological Diseases, Beijing, China.
³ Department of Neurology, Epilepsy Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
⁴ Beijing Institute for Brain Disorders, Beijing, China.
⁵ Department of Neurology, The First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, China.
⁶ Beijing Institute of Neurosurgery, Beijing, China.

Abstract

The white matter disease spectrum is associated with many genetic diseases, including AARS2, CADASIL, ALD, and others. In this study, to determine the novel alanyl-tRNA synthetase 2 mutation implicated in white matter disease, several families with an autosomal recessive inheritance pattern of white matter disease were analyzed by whole-exome sequencing. Variants were prioritized according to their rarity and pathogenic variants in genes already known to be associated with leukodystrophies and were confirmed by Sanger sequencing using standard protocols. We identified 5 rare variants (c.452T>C chr6:44279256 p.M151T, c.1871G>A chr6:44272054 p.W624X, c.802A>G chr6:44278128 p.M268V, c.1703-1704del chr6:-44272430-44272431 p.Q568fs, and c.179C>A chr6-44280882 p.P60H) with varying expression in 4 independent Chinese families with leukodystrophy. These single nucleotide variants (SNVs), or deletion mutations, each induced a frameshift, causing a missense mutation in alanyl-tRNA synthetase 2. These findings suggested that all mutations might contribute to the development of leukodystrophy in the examined family members. Combined with previous findings, our data confirmed that the novel mutations are located in leukodystrophy-related risk genes. We also summarized all the alanyl-tRNA synthetase 2 mutations related to the onset of leukodystrophies in adults.

Keywords: AARS2; leukodystrophies; mutation; pathogenic variants; white matter.