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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.
PMID
Related Publications

Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease.

Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.

Exome analysis identified a novel missense mutation in the CLPP gene in a consanguineous Saudi family expanding the clinical spectrum of Perrault Syndrome type-3.

Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.

Expanding the genotypic spectrum of Perrault syndrome.

Authors

Mayor MeshTerms

High-Throughput Nucleotide Sequencing

Keywords
Journal Title journal of human genetics
Publication Year Start




PMID- 26657938
OWN - NLM
STAT- MEDLINE
DA  - 20160425
DCOM- 20170330
LR  - 20170330
IS  - 1435-232X (Electronic)
IS  - 1434-5161 (Linking)
VI  - 61
IP  - 4
DP  - 2016 Apr
TI  - First independent replication of the involvement of LARS2 in Perrault syndrome by
      whole-exome sequencing of an Italian family.
PG  - 295-300
LID - 10.1038/jhg.2015.149 [doi]
AB  - 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.
FAU - Solda, Giulia
AU  - Solda G
AD  - Department of Biomedical Sciences, Humanitas University, Milan, Italy.
AD  - Humanitas Clinical and Research Center, Milan, Italy.
FAU - Caccia, Sonia
AU  - Caccia S
AD  - Department of Biomedical and Clinical Sciences "Luigi Sacco", Universita degli
      Studi di Milano - LITA Vialba, Milan, Italy.
FAU - Robusto, Michela
AU  - Robusto M
AD  - Department of Biomedical Sciences, Humanitas University, Milan, Italy.
AD  - Humanitas Clinical and Research Center, Milan, Italy.
FAU - Chiereghin, Chiara
AU  - Chiereghin C
AD  - Department of Biomedical Sciences, Humanitas University, Milan, Italy.
AD  - Humanitas Clinical and Research Center, Milan, Italy.
FAU - Castorina, Pierangela
AU  - Castorina P
AD  - UO Audiologia, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan,
      Italy.
FAU - Ambrosetti, Umberto
AU  - Ambrosetti U
AD  - UO Audiologia, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan,
      Italy.
AD  - Dipartimento di Scienze Cliniche e di Comunita, Universita degli Studi di Milano,
      Milan, Italy.
FAU - Duga, Stefano
AU  - Duga S
AD  - Department of Biomedical Sciences, Humanitas University, Milan, Italy.
AD  - Humanitas Clinical and Research Center, Milan, Italy.
FAU - Asselta, Rosanna
AU  - Asselta R
AD  - Department of Biomedical Sciences, Humanitas University, Milan, Italy.
AD  - Humanitas Clinical and Research Center, Milan, Italy.
LA  - eng
GR  - GGP11177/Telethon/Italy
PT  - Journal Article
DEP - 20151210
PL  - England
TA  - J Hum Genet
JT  - Journal of human genetics
JID - 9808008
RN  - 0 (Mitochondrial Proteins)
RN  - EC 3.4.21.92 (ClpP protein, human)
RN  - EC 3.4.21.92 (Endopeptidase Clp)
RN  - EC 3.6.4.- (DNA Helicases)
RN  - EC 3.6.4.12 (C10ORF2 protein, human)
RN  - EC 4.2.1.107 (Peroxisomal Multifunctional Protein-2)
RN  - EC 4.2.1.119 (HSD17B4 protein, human)
RN  - EC 6.1.1.- (Amino Acyl-tRNA Synthetases)
RN  - EC 6.1.1.21 (HARS2 protein, human)
RN  - EC 6.1.1.4 (LARS2 protein, human)
RN  - Gonadal dysgenesis XX type deafness
SB  - IM
MH  - Amino Acyl-tRNA Synthetases/*genetics
MH  - DNA Helicases/genetics
MH  - Endopeptidase Clp/genetics
MH  - Exome/genetics
MH  - Female
MH  - Gonadal Dysgenesis, 46,XX/*genetics/pathology
MH  - Hearing Loss, Sensorineural/*genetics/pathology
MH  - *High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - Italy
MH  - Mitochondrial Proteins/genetics
MH  - Mutation
MH  - Pedigree
MH  - Peroxisomal Multifunctional Protein-2/genetics
PMC - PMC4817218
MID - EMS66009
OID - NLM: EMS66009 [Available on 10/01/16]
OID - NLM: PMC4817218 [Available on 10/01/16]
EDAT- 2015/12/15 06:00
MHDA- 2017/03/31 06:00
CRDT- 2015/12/15 06:00
PHST- 2015/09/04 [received]
PHST- 2015/11/09 [revised]
PHST- 2015/11/10 [accepted]
AID - jhg2015149 [pii]
AID - 10.1038/jhg.2015.149 [doi]
PST - ppublish
SO  - J Hum Genet. 2016 Apr;61(4):295-300. doi: 10.1038/jhg.2015.149. Epub 2015 Dec 10.