JIMD Reports, Volume 28

Riley, Lisa G, Rudinger-Thirion, Joëlle, Schmitz-Abe, Klaus, Thorburn, David R, Davis, Ryan L, Teo, Juliana, Arbuckle, Susan, Cooper, Sandra T, Campagna, Dean R, Frugier, Magali, Markianos, Kyriacos, Sue, Carolyn M, Fleming, Mark D, Christodoulou, John, Riley, Lisa G., Thorburn, David R., Davis, Ryan L., Cooper, Sandra T., Campagna, Dean R., Sue, Carolyn M., Fleming, Mark D., Lisa G. Riley, Joëlle Rudinger-Thirion, Klaus Schmitz-Abe, David R. Thorburn, Ryan L. Davis, Juliana Teo, Susan Arbuckle, Sandra T. Cooper, Dean R. Campagna, Magali Frugier, Kyriacos Markianos, Carolyn M. Sue, Mark D. Fleming, John Christodoulou

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.