Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome.
An uncharacterized multisystemic mitochondrial cytopathy was diagnosed in two infants from consanguineous Palestinian kindred living in a single village. The most significant clinical findings were tubulopathy (hyperuricemia, metabolic alkalosis), pulmonary hypertension, and progressive renal failure in infancy (HUPRA syndrome). Analysis of the consanguineous pedigree suggested that the causative mutation is in the nuclear DNA. By using genome-wide SNP homozygosity analysis, we identified a homozygous identity-by-descent region on chromosome 19 and detected the pathogenic mutation c.1169A>G (p.Asp390Gly) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. The same homozygous mutation was later identified in a third infant with HUPRA syndrome. The carrier rate of this mutation among inhabitants of this Palestinian isolate was found to be 1:15. The mature enzyme catalyzes the ligation of serine to two mitochondrial tRNA isoacceptors: tRNA(Ser)(AGY) and tRNA(Ser)(UCN). Analysis of amino acylation of the two target tRNAs, extracted from immortalized peripheral lymphocytes derived from two patients, revealed that the p.Asp390Gly mutation significantly impacts on the acylation of tRNA(Ser)(AGY) but probably not that of tRNA(Ser)(UCN). Marked decrease in the expression of the nonacylated transcript and the complete absence of the acylated tRNA(Ser)(AGY) suggest that this mutation leads to significant loss of function and that the uncharged transcripts undergo degradation.
Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel.
Ruth
R
Belostotsky
Efrat
E
Ben-Shalom
Choni
C
Rinat
Rachel
R
Becker-Cohen
Sofia
S
Feinstein
Sharon
S
Zeligson
Reeval
R
Segel
Orly
O
Elpeleg
Suheir
S
Nassar
Yaacov
Y
Frishberg
D000472:Alkalosis, Respiratory / Q000235:genetics* / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology; D033461:Hyperuricemia / Q000235:genetics* / Q000473:pathology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency / Q000235:genetics* / Q000473:pathology; D012714:Serine-tRNA Ligase / Q000235:genetics*; D013577:Syndrome
D004272:DNA, Mitochondrial; D012346:RNA, Transfer, Amino Acyl; D012714:Serine-tRNA Ligase
Mol Genet Metab. 2003 May;79(1):1-5
12765840
Mol Genet Metab. 2010 Jun;100(2):111-7
20359921
Nat Genet. 2007 Apr;39(4):534-9
17384640
RNA. 2000 Oct;6(10):1356-79
11073213
J Biol Chem. 2000 Jun 30;275(26):19913-20
10764807
J Mol Biol. 1994 Mar 4;236(4):982-9
8120906
Am J Hum Genet. 2010 Jul 9;87(1):52-9
20598274
Respir Med. 2003 Feb;97(2):130-3
12587962
EMBO J. 2005 Oct 5;24(19):3369-79
16163389
Am J Hum Genet. 2007 Oct;81(4):857-62
17847012
J Biol Chem. 2001 Dec 14;276(50):46770-8
11577083
J Biol Chem. 1991 Dec 25;266(36):24712-8
1761566
Nucleic Acids Res. 2008 Dec;36(22):7192-206
19004874
Biochem Biophys Res Commun. 2004 May 7;317(3):774-8
15081407
Methods Enzymol. 2008;449:221-37
19215761
Mol Genet Metab. 2006 Sep-Oct;89(1-2):3-13
16854608
Acta Biochim Biophys Sin (Shanghai). 2009 Mar;41(3):179-87
19280056
Eur J Neurol. 2009 Dec;16(12):1255-64
19950421
Eur J Hum Genet. 2001 May;9(5):385-7
11378827
Kidney Int. 2001 Mar;59(3):846-54
11231339
Biochem J. 2003 Aug 15;374(Pt 1):131-6
12737626
QJM. 2008 Oct;101(10):755-66
18487272
J Med Genet. 2006 Sep;43(9):e46
16950817