LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure

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

doi:10.1007/8904_2015_515

Cited by 57 publications

(41 citation statements)

References 29 publications

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“…For example, mutations in mitochondrial ARS enzymes that cause recessive diseases can directly affect protein solubility [74] or impair mitochondrial protein translation [4,5,46,50,56–59,63,75–79], consistent with a loss-of-function effect. With respect to ARS mutations that cause dominant peripheral neuropathy, structural analyses have revealed that the majority of GARS mutations affect residues within the dimer interface [80].…”

Section: Models To Study the Mechanism Of Ars Mutations In Human Diseasementioning

confidence: 99%

Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations

Oprescu

Griffin

Beg

et al. 2017

Methods

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Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for charging tRNA with cognate amino acids—the first step in protein synthesis. ARSs are required for protein translation in the cytoplasm and mitochondria of all cells. Surprisingly, mutations in 28 of the 37 nuclear-encoded human ARS genes have been linked to a variety of recessive and dominant tissue-specific disorders. Current data sustains that impaired enzyme function is a robust predictor of the pathogenicity of ARS mutations. However, experimental model systems that distinguish between pathogenic and non-pathogenic ARS variants are required for implicating newly identified ARS mutations in disease. Here, we outline strategies to assist in predicting the pathogenicity of ARS variants and urge cautious evaluation of genetic and functional data prior to linking an ARS mutation to a human disease phenotype.

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Section: Models To Study the Mechanism Of Ars Mutations In Human Diseasementioning

confidence: 99%

Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations

Oprescu

Griffin

Beg

et al. 2017

Methods

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“…In a study of 35 multi-ethnic patients carrying a TMEM70 mutation, 35% manifested with renal disease in the form of RTA, hydronephrosis and acute or chronic renal failure (69). In a newborn girl with MIMODS due to a mutation in the LARS2 gene, encoding for a mitochondrial amino-acyl-tRNA synthetase, progressive renal failure was responsible for mortality 5 days after birth (70). In three children from the same consanguineous parents, antenatal skin oedema, hypotonia, cardiomyopathy and tubulopathy were attributed to mutations in the MRPS22 gene (71).…”

Section: Mdsmentioning

confidence: 99%

Renal manifestations of primary mitochondrial disorders

Finsterer

Scorza

2017

Biomedical Reports

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“…Somatic mutations in SF3B1 are found in ≥80% of patients, sometimes in combination with mutations in other genes, including JAK2V617F, ASXL1, DNMT3A, SETBP1 , and TET2 . Congenital SA is associated with mutations in nuclear genes involved in heme biosynthesis ( ALAS2 and SLC25A38 ), iron‐sulfur‐cluster biogenesis/transport ( ABCB7 and GLRX5 ), thiamine‐transport protein ( SLC19A1 ), structural subunits of the respiratory chain complex ( NDUFB11 ), and mitochondrial protein synthesis and chaperones ( PUS1, YARS2, LARS2 , and HSPA9 ) or with mutations in mitochondrial DNA ( MTATP6 , or large mtDNA deletions) involved in mitochondrial biogenesis …”

Section: Introductionmentioning

confidence: 99%

Sideroblastic anemia associated with multisystem mitochondrial disorders

Tesařová

Vondráčková

Stufkova

et al. 2018

Pediatric Blood & Cancer

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Background Sideroblastic anemia represents a heterogeneous group of inherited or acquired diseases with disrupted erythroblast iron utilization, ineffective erythropoiesis, and variable systemic iron overload. In a cohort of 421 patients with multisystem mitochondrial diseases, refractory anemia was found in 8 children. Results Five children had sideroblastic anemia with increased numbers of ring sideroblasts >15%. Two of the children had a fatal course of MLASA1 syndrome (mitochondrial myopathy, lactic acidosis, and sideroblastic anemia [SA]) due to a homozygous, 6‐kb deletion in the PUS1 gene, part of the six‐member family of pseudouridine synthases (pseudouridylases). Large homozygous deletions represent a novel cause of presumed PUS1‐loss‐of‐function phenotype. The other three children with SA had Pearson syndrome (PS) due to mtDNA deletions of 4 to 8 kb; two of these children showed early onset of PS and died due to repeated sepsis; the other child had later onset of PS and survived as the hematological parameters normalized and the disease transitioned to Kearns–Sayre syndrome. In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor. Conclusions Sideroblastic anemia was found in fewer than 1.2% of patients with multisystem mitochondrial disease, and it was usually associated with an unfavorable prognosis.

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LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure

Abstract: Pathogenic variants in mitochondrial aminoacyltRNA synthetases result in a broad range of mitochondrial respiratory chain disorders despite their shared role in mitochondrial protein synthesis.

Cited by 57 publications

References 29 publications

Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations

Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations

Renal manifestations of primary mitochondrial disorders

Sideroblastic anemia associated with multisystem mitochondrial disorders

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