title: LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure.
abstract: Pathogenic variants in mitochondrial aminoacyl-tRNA synthetases result in a broad range of mitochondrial respiratory chain disorders despite their shared role in mitochondrial protein synthesis. LARS2 encodes the mitochondrial leucyl-tRNA synthetase, which attaches leucine to its cognate tRNA. Sequence variants in LARS2 have previously been associated with Perrault syndrome, characterized by premature ovarian failure and hearing loss (OMIM #615300). In this study, we report variants in LARS2 that are associated with a severe multisystem metabolic disorder. The proband was born prematurely with severe lactic acidosis, hydrops, and sideroblastic anemia. She had multisystem complications with hyaline membrane disease, impaired cardiac function, a coagulopathy, pulmonary hypertension, and progressive renal disease and succumbed at 5 days of age. Whole exome sequencing of patient DNA revealed compound heterozygous variants in LARS2 (c.1289C>T; p.Ala430Val and c.1565C>A; p.Thr522Asn). The c.1565C>A (p.Thr522Asn) LARS2 variant has previously been associated with Perrault syndrome and both identified variants are predicted to be damaging (SIFT, PolyPhen). Muscle and liver samples from the proband did not display marked mitochondrial respiratory chain enzyme deficiency. Immunoblotting of patient muscle and liver showed LARS2 levels were reduced in liver and complex I protein levels were reduced in patient muscle and liver. Aminoacylation assays revealed p.Ala430Val LARS2 had an 18-fold loss of catalytic efficiency and p.Thr522Asn a 9-fold loss compared to wild-type LARS2. We suggest that the identified LARS2 variants are responsible for the severe multisystem clinical phenotype seen in this baby and that mutations in LARS2 can result in variable phenotypes.
authors.affiliation: Genetic Metabolic Disorders Research Unit, Kids Research Institute, Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. lisa.riley@health.nsw.gov.au.|Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. lisa.riley@health.nsw.gov.au.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Riley
authors.affiliation: Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, Strasbourg, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Rudinger-Thirion
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.|Broad Institute, Cambridge, MA, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmitz-Abe
authors.affiliation: Department of Paediatrics, Murdoch Children's Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: Department of Neurogenetics, Kolling Institute of Medical Research, University of Sydney and Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Davis
authors.affiliation: Department of Haematology, Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Juliana
authors.initials: J
authors.lastname: Teo
authors.affiliation: Department of Pathology, Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Arbuckle
authors.affiliation: Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|Institute for Neuroscience and Muscle Research, Kids Research Institute, Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Cooper
authors.affiliation: Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Dean R
authors.initials: DR
authors.lastname: Campagna
authors.affiliation: Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, Strasbourg, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Frugier
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Markianos
authors.affiliation: Department of Neurogenetics, Kolling Institute of Medical Research, University of Sydney and Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
authors.affiliation: Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.affiliation: Genetic Metabolic Disorders Research Unit, Kids Research Institute, Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia.|Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou