title: First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.
abstract: Perrault syndrome (MIM #233400) is a rare autosomal recessive disorder characterized by ovarian dysgenesis and primary ovarian insufficiency in females, and progressive hearing loss in both genders. Recently, mutations in five genes (HSD17B4, HARS2, CLPP, LARS2 and C10ORF2) were found to be responsible for Perrault syndrome, although they do not account for all cases of this genetically heterogeneous condition. We used whole-exome sequencing to identify pathogenic variants responsible for Perrault syndrome in an Italian pedigree with two affected siblings. Both patients were compound heterozygous for two novel missense variants within the mitochondrial leucyl-tRNA synthetase (LARS2): NM_015340.3:c.899C>T(p.Thr300Met) and c.1912G>A(p.Glu638Lys). Both variants cosegregated with the phenotype in the family. p.Thr300 and p.Glu638 are evolutionarily conserved residues, and are located, respectively, within the editing domain and immediately before the catalytically important KMSKS motif. Homology modeling using as template the E. coli leucyl-tRNA synthetase provided further insights on the possible pathogenic effects of the identified variants. This represents the first independent replication of the involvement of LARS2 mutations in Perrault syndrome, contributing valuable information for the further understanding of this disease.
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Milan, Italy.|Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Soldà
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli Studi di Milano - LITA Vialba, Milan, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Caccia
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Milan, Italy.|Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Robusto
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Milan, Italy.|Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Chiereghin
authors.affiliation: UO Audiologia, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Pierangela
authors.initials: P
authors.lastname: Castorina
authors.affiliation: UO Audiologia, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.|Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Ambrosetti
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Milan, Italy.|Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Milan, Italy.|Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D049071:Endopeptidase Clp / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007558:Italy; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D064029:Peroxisomal Multifunctional Protein-2 / Q000235:genetics
chemical_list: D024101:Mitochondrial Proteins; C568646:ClpP protein, human; D049071:Endopeptidase Clp; D004265:DNA Helicases; C431576:TWNK protein, human; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human; D000604:Amino Acyl-tRNA Synthetases; C093612:HARS2 protein, human; C549096:LARS2 protein, human