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SERYL-tRNA SYNTHETASE 2; SARS2

SERYL-tRNA SYNTHETASE 2; SARS2

Alternative titles; symbolsSERYL-tRNA SYNTHETASE, MITOCHONDRIALMITOCHONDRIAL SERRSHGNC Approved Gene Symbol: SARS2Cytogenetic location: 19q13.2 Genomic coord...

Alternative titles; symbols

  • SERYL-tRNA SYNTHETASE, MITOCHONDRIAL
  • MITOCHONDRIAL SERRS

HGNC Approved Gene Symbol: SARS2

Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:38,915,265-38,930,762 (from NCBI)

▼ Description
The SARS2 gene encodes mitochondrial seryl-tRNA synthetase, which provides serine aminoacylation to 2 mitochondrial tRNAs, tRNA-ser(AGY) and tRNA-ser(UCN) (summary by Belostotsky et al., 2011).

▼ Cloning and Expression
By searching databases for aminoacyl-tRNA synthetases containing a mitochondrial targeting sequence, Bonnefond et al. (2005) identified SARS2, which they called mitochondrial SERRS. The deduced 518-amino acid protein has an N-terminal mitochondrial targeting signal with a predicted cleavage site after residue 20. SARS2 has characteristics of a class II mitochondrial aminoacyl-tRNA synthetase and is expected to function as a dimer.

Based on the cDNA sequence of bovine mitochondrial SerRS, Yokogawa et al. (2000) identified and cloned cDNAs of human and mouse SARS2 by RT-PCR. Comparison of protein sequences revealed that mammalian mitochondrial SerRS has a long C-terminal sequence with relatively high homology with prokaryotic SerRS. Because all known SerRS have an alpha-2 subunit structure, bovine mitochondrial SerRS was thought to exist as a dimer.

▼ Gene Structure
Bonnefond et al. (2005) determined that the SARS2 gene contains 16 exons and spans 15.1 kb.

▼ Mapping
By genomic sequence analysis, Bonnefond et al. (2005) mapped the SARS2 gene to chromosome 19.

By database search, Yokogawa et al. (2000) mapped the SARS gene to chromosome 19q13.1.

▼ Gene Function
Using purified protein from bovine liver mitochondria, Yokogawa et al. (2000) demonstrated that the single bovine mitochondrial SerRS recognized and aminoacylated both serine tRNAs (tRNAsSer), which have different structures, present in animal mitochondrial protein synthesis systems.

▼ Biochemical Features
Chimnaronk et al. (2005) determined the crystal structure of bovine mitochondrial Sars2 at 1.65-angstrom resolution. There are 2 auxiliary extensions in both N and C termini of the enzyme that overlap the tRNA-binding site. This clash, combined together with mutational analysis, showed a distinct mechanism for enzyme recognition of tRNA-ser(UCN) and tRNA-ser(AGY) by 3 separate regions of the enzyme: the distal helix, the C-terminal tail, and a narrow positively charged patch on the N-terminal helical arm of Sars2. The results illustrated the distinct set of residues responsible for recognition of the 2 cognate mitochondrial tRNA-Ser, defined by their isoacceptor codons AGY and UCN. Chimnaronk et al. (2005) suggested that this was an unprecedented mechanism of a dual-mode recognition that can discriminate 2 distinct mitochondrial tRNA-Ser by alternative combination of interaction sites in mammalian mitochondria.

▼ Molecular Genetics
In an infant boy, born of nonconsanguineous Palestinian parents, with HUPRA syndrome (HUPRAS; 613845), Belostotsky et al. (2011) identified a homozygous mutation in the SARS2 gene (D390G; 612804.0001). Within the extended family, in an infant girl with HUPRA syndrome, born of first-cousin Palestinian parents, the authors identified homozygosity for the same D390G mutation. A third infant with a similar disorder from an unrelated Palestinian family from the same village was also found to carry the same homozygous mutation. The phenotype was a multisystem disorder, characterized by prematurity, progressive renal failure leading to electrolyte imbalances, metabolic alkalosis, and pulmonary hypertension. The molecular defect was predicted to adversely affect mitochondrial translation systems and lead to derangements in the synthesis of mitochondrial proteins and thus in energy supply. Some residual activity of the mutated enzyme may have been able to maintain most tissues above their necessary threshold, but failed to do so in tissues with high energy requirement, such as the thick ascending limb of the loop of Henle.

In 2 Spanish sibs with HUPRA syndrome, Rivera et al. (2013) identified a homozygous missense mutation in the SARS2 gene (R402H; 613845.0002). The mutation, which was identified by direct gene sequencing, segregated with the disorder in the family. Respiratory chain enzyme testing was normal in muscle tissue from both sibs, but in one of the sibs, testing showed mildly reduced function of complexes I and IV in cultured skin fibroblasts.

In a 10-year-old boy with spastic tetraparesis without known kidney disease or abnormalities in acid-base balance, Linnankivi et al. (2016) identified homozygosity for a c.1347G-A transversion (NM_017827.3) at the last nucleotide in exon 14 of the SARS2 gene (rs200404654), predicted to affect a donor splice site. The mutation, which was found by next-generation sequencing of a mitochondrial disease gene panel, was present in heterozygous state in the parents. The variant was present in heterozygous state in the ExAC database. Testing in patient fibroblasts showed that the mutation resulted in retention of intron 14 in the majority of SARS2 cDNA, which was predicted to lead to a frameshift and a premature stop codon at residue 510. mtSerRs protein expression was also found to be significantly reduced. mtSerRs aminoacylates both tRNA-ser(AGY) and tRNA-ser(UCN), and studies in patient fibroblasts showed a reduction of tRNA-ser(AGY) levels, whereas tRNA-ser(UCN) levels were mostly unaffected. Linnankivi et al. (2016) suggested that the stable level of tRNA-ser(UCN) may account for the difference between the phenotype of this patient and previously reported HUPRA patients.

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 HYPERURICEMIA, PULMONARY HYPERTENSION, RENAL FAILURE, AND ALKALOSIS SYNDROME
SARS2, ASP390GLY
In an infant boy, born of nonconsanguineous Palestinian parents, with HUPRA syndrome (HUPRAS; 613845), Belostotsky et al. (2011) identified a homozygous 1169A-G transition in exon 13 of the SARS2 gene, resulting in an asp390-to-gly (D390G) substitution in the C-terminal globular domain in the second of 8 beta-strands that assemble the active site. Within the extended family, in an infant girl with HUPRA syndrome, born of first-cousin Palestinian parents, the authors identified homozygosity for the same D390G mutation. A third infant with a similar disorder from an unrelated Palestinian family from the same village was also found to carry the same homozygous mutation, and a year earlier, the mother had given birth to a premature girl, who suffered from pulmonary hypertension and died of respiratory failure at age 39 days. All 3 sets of parents were heterozygous for the D390G mutation. The mutation was not found in 212 control chromosomes from individuals of Palestinian descent, but was found in 7 of 103 DNA samples from individuals from the same village as the patients, indicating a high carrier rate of 1:15. HUPRA syndrome is a multisystem disorder, characterized by prematurity, progressive renal failure leading to electrolyte imbalances, metabolic alkalosis, and pulmonary hypertension. The molecular defect was predicted to adversely affect mitochondrial translation systems and lead to derangements in the synthesis of mitochondrial proteins and thus in energy supply. Studies in patient lymphoblastoid cells showed that the amount of total tRNA-ser(AGY) was reduced to 10 to 20% of controls, whereas the amount of tRNA-ser(UCN) was similar to controls. There was a marked decrease in the expression of the nonacylated transcript and a complete absence of the acylated tRNA-Ser(AGY), suggesting that the D390G mutation leads to significant loss of function and that the uncharged transcripts are degraded.

.0002 HYPERURICEMIA, PULMONARY HYPERTENSION, RENAL FAILURE, AND ALKALOSIS SYNDROME
SARS2, ARG402HIS
In 2 sibs, born of nonconsanguineous Spanish parents, with HUPRA syndrome (HUPRAS; 613845), Rivera et al. (2013) identified a homozygous c.1205G-A transition in the SARS2 gene, resulting in an arg402-to-his (R402H) substitution at a highly conserved residue in the C-terminal globular domain. The mutation, which was identified by direct gene sequencing, segregated with the disorder in the family. The mutation had a low frequency in the Exome Sequencing Project database, being described only twice in heterozygous state. Protein modeling showed a close spatial location between R402H and the previously reported pathogenic mutation in SARS2 (D390G; 613845.0001). Respiratory chain enzyme testing was normal in muscle tissue from both sibs, but in one of the sibs, testing showed mildly reduced function of complexes I and IV in cultured skin fibroblasts.

Tags: 19q13.2