title: Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.
abstract: The genetic causes of premature ovarian failure (POF) are highly heterogeneous, and causative mutations have been identified in more than ten genes so far. In two families affected by POF accompanied by hearing loss (together, these symptoms compose Perrault syndrome), exome sequencing revealed mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase: homozygous c.1565C>A (p.Thr522Asn) in a consanguineous Palestinian family and compound heterozygous c.1077delT and c.1886C>T (p.Thr629Met) in a nonconsanguineous Slovenian family. LARS2 c.1077delT leads to a frameshift at codon 360 of the 901 residue protein. LARS2 p.Thr522Asn occurs in the LARS2 catalytic domain at a site conserved from bacteria through mammals. LARS2 p.Thr629Met occurs in the LARS2 leucine-specific domain, which is adjacent to a catalytic loop critical in all species but for which primary sequence is not well conserved. A recently developed method of detecting remote homologies revealed threonine at this site in consensus sequences derived from multiple-species alignments seeded by human and E. coli residues at this region. Yeast complementation indicated that LARS2 c.1077delT is nonfunctional and that LARS2 p.Thr522Asn is partially functional. LARS2 p.Thr629Met was functional in this assay but might be insufficient as a heterozygote with the fully nonfunctional LARS2 c.1077delT allele. A known C. elegans strain with the protein-truncating alteration LARS-2 p.Trp247Ter was confirmed to be sterile. After HARS2, LARS2 is the second gene encoding mitochondrial tRNA synthetase to be found to harbor mutations leading to Perrault syndrome, further supporting a critical role for mitochondria in the maintenance of ovarian function and hearing.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle WA 98195, USA. sbpierce@uw.edu
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Pierce
authors.forename: Ksenija
authors.initials: K
authors.lastname: Gersak
authors.forename: Rachel
authors.initials: R
authors.lastname: Michaelson-Cohen
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Daniel
authors.initials: D
authors.lastname: Malach
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Klevit
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D023961:Gonadal Dysgenesis, 46,XX / Q000150:complications / Q000235:genetics*; D034381:Hearing Loss / Q000209:etiology*; D006319:Hearing Loss, Sensorineural / Q000150:complications / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007935:Leucine-tRNA Ligase / Q000235:genetics*; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016649:Primary Ovarian Insufficiency / Q000209:etiology*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D000604:Amino Acyl-tRNA Synthetases; C549096:LARS2 protein, human; D007935:Leucine-tRNA Ligase
references.citation: Am J Hum Genet. 2013 Apr 4;92(4):605-13
references.pmid: 23541340
references.citation: Nat Struct Mol Biol. 2012 Jun 10;19(7):677-84
references.pmid: 22683997
references.citation: Am J Hum Genet. 2011 Oct 7;89(4):572-9
references.pmid: 21963259
references.citation: Am J Hum Genet. 2007 Sep;81(3):576-81
references.pmid: 17701902
references.citation: Am J Hum Genet. 1998 Mar;62(3):533-41
references.pmid: 9497258
references.citation: EMBO J. 1988 Feb;7(2):473-83
references.pmid: 3284745
references.citation: Mol Hum Reprod. 2002 Aug;8(8):729-33
references.pmid: 12149404
references.citation: PLoS Biol. 2012;10(3):e1001288
references.pmid: 22448145
references.citation: EMBO J. 2000 May 15;19(10):2351-61
references.pmid: 10811626
references.citation: Am J Hum Genet. 2006 Jul;79(1):113-9
references.pmid: 16773570
references.citation: Hum Mol Genet. 2012 Oct 15;21(20):4521-9
references.pmid: 22833457
references.citation: N Engl J Med. 2009 Mar 19;360(12):1200-10
references.pmid: 19246354
references.citation: Biochim Biophys Acta. 2000 Feb 29;1490(3):245-58
references.pmid: 10684970
references.citation: Cell. 2012 Feb 17;148(4):716-26
references.pmid: 22341444
references.citation: Annu Rev Genomics Hum Genet. 2008;9:87-107
references.pmid: 18767960
references.citation: Reproduction. 2011 May;141(5):549-61
references.pmid: 21339285
references.citation: Am J Hum Genet. 2010 Aug 13;87(2):282-8
references.pmid: 20673864
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6543-8
references.pmid: 21464306
references.citation: Nat Genet. 2003 Jan;33(1):40-8
references.pmid: 12447374
references.citation: Genes Dev. 1992 Mar;6(3):380-9
references.pmid: 1532158
references.citation: RNA. 2007 Aug;13(8):1184-90
references.pmid: 17585048
references.citation: Am J Hum Genet. 2004 Jul;75(1):106-11
references.pmid: 15136966
references.citation: Brain. 2012 May;135(Pt 5):1387-94
references.pmid: 22492562
references.citation: Neurobiol Aging. 2008 Jul;29(7):1080-92
references.pmid: 17363114
references.citation: Cell. 1995 Sep 22;82(6):959-68
references.pmid: 7553856
references.citation: J Med Genet. 2012 Apr;49(4):234-41
references.pmid: 22499341
references.citation: Annu Rev Genet. 2011;45:299-329
references.pmid: 21910628
references.citation: Am J Hum Genet. 2010 Jul 9;87(1):90-4
references.pmid: 20602914
references.citation: Nat Methods. 2011 Dec 25;9(2):173-5
references.pmid: 22198341
references.citation: Am J Hum Genet. 2008 Jun;82(6):1342-8
references.pmid: 18499083
references.citation: Bioinformatics. 2012 Dec 15;28(24):3240-7
references.pmid: 23080114