Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease
Adult; Biochemistry & Molecular Biology; Catalytic Domain; Child; Female; gene; Genetic Diseases; Genetic Predisposition to Disease; Genetics & Heredity; Hearing Loss; Heterozygote; Homozygote; Humans; impairment; Inborn; Infant; lactic-acidosis; Loss of Function Mutation; Male; mechanisms; Mutation; myopathy; Newborn; onset; Pedigree; Phenotype; phenotypic variability; Preschool; recessive mutations; Sensorineural; Severity of Illness Index; swiss-model; Tyrosine-tRNA Ligase; variant; Whole Exome Sequencing; Yeasts
Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.
Williams Katie B; Brigatti Karlla W; Puffenberger Erik G; Gonzaga-Jauregui Claudia; Griffin Laurie B; Martinez Erick D; Wenger Olivia K; Yoder Mark A; Kandula Vinay V R; Fox Michael D; Demczko Matthew M; Poskitt Laura; Furuya Katryn N; Reid Jeffrey G; Overton John D; Baras Aris; Miles Lili; Radhakrishnan Kadakkal; Carson Vincent J; Antonellis Anthony; Jinks Robert N; Strauss Kevin A
Human Molecular Genetics
2019
1905-7
<a href="http://doi.org/10.1093/hmg/ddy344" target="_blank" rel="noreferrer noopener">10.1093/hmg/ddy344</a>
Comparison Of Dopamine To Dobutamine And Norepinephrine For Oxygen Delivery And Uptake In Septic Shock
agents; cardiac-output; catecholamines; consumption; dobutamine; dopamine; General & Internal Medicine; hemodynamics; infusion; inotropic; intra-pulmonary shunt; lactic-acidosis; norepinephrine; oxygen consumption; septic shock; severe sepsis; skeletal-muscle; therapy; transport
Objectives: To test whether dopamine infusion improves oxygen delivery (D over dot O-2) and oxygen uptake (V over dot O-2) in hyperdynamic septic shock patients stabilized by adequate volume and dobutamine alone, or by the combination of dobutamine and norepinephrine. Design: Prospective clinical trial of two patient groups. Group 1 (n = 15) was stabilized with dobutamine, and group 2 (n = 10) was stabilized with dobutamine and norepinephrine. Setting: Intensive care unit in a university hospital. Patients: Twenty-five postoperative, hyperdynamic septic shock patients. Interventions: The stabilizing catecholamine infusion was replaced in a stepwise manner by dopamine to achieve a similar mean arterial pressure (dopamine doses: group 1, mean 22 +/- 15 mu g/kg/min [range 6 to 52]; and group 2, mean 57 +/- 41 mu g/kg/min [range 15 to 130]). Measurements and Main Results: A complete hemodynamic profile was performed with oxygen transport-related variables at baseline, after replacement by dopamine and after resetting to the original catecholamine infusion. The change to dopamine resulted in increases in cardiac index (group 1: 20% [p < .01]; group 2: 33% [p < .01]), and D over dot O-2 (group 1: 19% [p < .01]; group 2: 27% [p < .01]). However, V over dot O-2, whether directly measured from the respiratory gases or calculated by the cardiovascular Fick principle, did not change in both groups with dopamine, while the oxygen extraction ratio decreased significantly in both groups with dopamine. Heart rate, pulmonary artery occlusion pressure, and pulmonary shunt fraction all increased with dopamine, Pao(2) decreased, but oxygen saturation remained stable in both groups with dopamine. Conclusions: Short-term dopamine infusion in hyperdynamic septic shock patients, de. spite producing higher global D over dot O-2, was not superior to dobutamine or the combination of dobutamine and norepinephrine infusion.
Hannemann L; Reinhart K; Grenzer O; Meierhellmann A; Bredle D L
Critical Care Medicine
1995
1995-12
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1097/00003246-199512000-00004" target="_blank" rel="noreferrer noopener">10.1097/00003246-199512000-00004</a>