title: Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.
abstract: Perrault syndrome is a genetically heterogeneous recessive disorder characterized by ovarian dysgenesis and sensorineural hearing loss. In a nonconsanguineous family with five affected siblings, linkage analysis and genomic sequencing revealed the genetic basis of Perrault syndrome to be compound heterozygosity for mutations in the mitochondrial histidyl tRNA synthetase HARS2 at two highly conserved amino acids, L200V and V368L. The nucleotide substitution creating HARS2 p.L200V also created an alternate splice leading to deletion of 12 codons from the HARS2 message. Affected family members thus carried three mutant HARS2 transcripts. Aminoacylation activity of HARS2 p.V368L and HARS2 p.L200V was reduced and the deletion mutant was not stably expressed in mammalian mitochondria. In yeast, lethality of deletion of the single essential histydyl tRNA synthetase HTS1 was fully rescued by wild-type HTS1 and by HTS1 p.L198V (orthologous to HARS2 p.L200V), partially rescued by HTS1 p.V381L (orthologous to HARS2 p.V368L), and not rescued by the deletion mutant. In Caenorhabditis elegans, reduced expression by RNAi of the single essential histydyl tRNA synthetase hars-1 severely compromised fertility. Together, these data suggest that Perrault syndrome in this family was caused by reduction of HARS2 activity. These results implicate aberrations of mitochondrial translation in mammalian gonadal dysgenesis. More generally, the relationship between HARS2 and Perrault syndrome illustrates how causality may be demonstrated for extremely rare inherited mutations in essential, highly conserved genes.
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195, USA.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Pierce
authors.forename: Karen M
authors.initials: KM
authors.lastname: Chisholm
authors.forename: Eric D
authors.initials: ED
authors.lastname: Lynch
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: John M
authors.initials: JM
authors.lastname: Opitz
authors.forename: Weiqing
authors.initials: W
authors.lastname: Li
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Klevit
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D019943:Amino Acid Substitution; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics; D023961:Gonadal Dysgenesis, 46,XX / Q000201:enzymology / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000201:enzymology / Q000235:genetics; D006643:Histidine-tRNA Ligase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics
chemical_list: D024101:Mitochondrial Proteins; D000604:Amino Acyl-tRNA Synthetases; C093612:HARS2 protein, human; C482538:HTS1 protein, S cerevisiae; D006643:Histidine-tRNA Ligase