Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect

2017 ◽  
Vol 91 (6) ◽  
pp. 918-923 ◽  
Author(s):  
D. Verrigni ◽  
D. Diodato ◽  
M. Di Nottia ◽  
A. Torraco ◽  
E. Bellacchio ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Novel Mutations ◽  
Respiratory Chain Defect ◽  
Mitochondrial Respiratory

scholarly journals Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3’-end processing

2018 ◽  
Author(s):  
Makenzie Saoura ◽  
Christopher A. Powell ◽  
Robert Kopajtich ◽  
Ahmad Alahmad ◽  
Haya H. AL-Balool ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Respiratory Chain ◽  
Mitochondrial Gene ◽  
Mitochondrial Respiratory Chain ◽  
Rna Metabolism ◽  
Mitochondrial Rna ◽  
Functional Link ◽  
Rnase Z ◽  
Mitochondrial Respiratory

AbstractDysfunction of mitochondrial gene expression, caused by mutations in either the mitochondrial or nuclear genomes, is associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism. For instance, pathogenic mutations have been identified in the genes encoding enzymes involved in the precursor transcript processing, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, which is responsible for endonucleolytic cleavage of the 3’ ends of mitochondrial pre-tRNAs. Here, we report the identification of sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy and lactic acidosis. We provided further evidence for the pathogenicity of the three previously reported variants by studying the RNase Z activity in an in vitro system and applied this recombinant system to investigate all novel missense variants, confirming the pathogenic role of these new ELAC2 mutations. We also modelled the residues affected by missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the individuals with novel ELAC2 variants have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of hypertrophic cardiomyopathy and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, possibly indicating a functional link between tumorigenesis and mitochondrial RNA metabolism.

scholarly journals Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease

2019 ◽  
Vol 28 (22) ◽  
pp. 3766-3776 ◽  
Author(s):  
Monika Oláhová ◽  
Camilla Ceccatelli Berti ◽  
Jack J Collier ◽  
Charlotte L Alston ◽  
Elisabeth Jameson ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Sensorineural Deafness ◽  
Early Death ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Respiratory Chain Enzyme ◽  
Cultured Fibroblasts ◽  
Respiratory Chain Defect ◽  
Heterozygous Variant ◽  
Mitochondrial Respiratory

Abstract BCS1L encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which has a known role in the assembly of Complex III of the mitochondrial respiratory chain. Phenotypes reported in association with pathogenic BCS1L variants include growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE syndrome), and Björnstad syndrome, characterized by abnormal flattening and twisting of hair shafts (pili torti) and hearing problems. Here we describe two patients harbouring biallelic variants in BCS1L; the first with a heterozygous variant c.166C>T, p.(Arg56*) together with a novel heterozygous variant c.205C>T, p.(Arg69Cys) and a second patient with a novel homozygous c.325C>T, p.(Arg109Trp) variant. The two patients presented with different phenotypes; the first patient presented as an adult with aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties. The second patient was an infant who presented with a classical GRACILE syndrome leading to death at 4 months of age. A decrease in BCS1L protein levels was seen in both patients, and biochemical analysis of Complex III revealed normal respiratory chain enzyme activities in the muscle of both patients. A decrease in Complex III assembly was detected in the adult patient’s muscle, whilst the paediatric patient displayed a combined mitochondrial respiratory chain defect in cultured fibroblasts. Yeast complementation studies indicate that the two missense variants, c.205C>T, p.(Arg69Cys) and c.325C>T, p.(Arg109Trp), impair the respiratory capacity of the cell. Together, these data support the pathogenicity of the novel BCS1L variants identified in our patients.

Mitochondrial respiratory chain defect: a new etiology for neonatalcholestasis and early liver insufficiency

1995 ◽  
Vol 23 (3) ◽  
pp. 290-294
Author(s):  
Isabel Goncalves ◽  
Dominique Hermans ◽  
Dominique Chretien ◽  
Pierre Rustin ◽  
Arnold Munnich ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Liver Insufficiency ◽  
Respiratory Chain Defect ◽  
Mitochondrial Respiratory

Biventricular non-compaction hypertrophic cardiomyopathy in association with congenital complete heart block and type I mitochondrial complex deficiency

2014 ◽  
Vol 25 (5) ◽  
pp. 1019-1021 ◽  
Author(s):  
Ranjana Dhar ◽  
William Reardon ◽  
Colin J. McMahon
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Respiratory Chain ◽  
Heart Block ◽  
Complete Heart Block ◽  
Mitochondrial Respiratory Chain ◽  
Type I ◽  
Skeletal Muscle Biopsy ◽  
Respiratory Chain Deficiency ◽  
Congenital Complete Heart Block ◽  
Mitochondrial Respiratory

AbstractWe report a baby girl with an antenatal diagnosis of biventricular non-compaction and complete heart block detected at 22 weeks’ gestation. Postnatal echocardiography confirmed severe biventricular non-compaction hypertrophic cardiomyopathy, multiple muscular ventricular septal defects, and mild–moderate pulmonary valve stenosis. Skeletal muscle biopsy confirmed complex 1 mitochondrial respiratory chain deficiency. An epicardial VVI pacemaker was implanted on day 3 of life and revised at 7 years of age. She remains stable at 8 years of age following pacing and medical treatment with carvedilol, aspirin, co-enzyme Q10, and carnitine. This represents the first report of biventricular non-compaction hypertrophic phenotype in association with congenital complete heart block and complex 1 mitochondrial respiratory chain deficiency in a child.

scholarly journals Secondary Mitochondrial Respiratory Chain Defect Can Delay Accurate PFIC2 Diagnosis

2013 ◽  
pp. 17-21 ◽  
Author(s):  
Anne Davit-Spraul ◽  
Marine Beinat ◽  
Dominique Debray ◽  
Agnes Rötig ◽  
Abdelhamid Slama ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Respiratory Chain Defect ◽  
Mitochondrial Respiratory

Molecular diagnosis in mitochondrial respiratory chain deficiency using exome sequencing

2013 ◽  
Vol 44 (02) ◽  
Author(s):  
R Kopajtich ◽  
T Haack ◽  
B Haberberger ◽  
J Mayr ◽  
W Sperl ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Respiratory Chain ◽  
Molecular Diagnosis ◽  
Mitochondrial Respiratory Chain ◽  
Respiratory Chain Deficiency ◽  
Mitochondrial Respiratory

333-LB: Impact of Aging on Mitochondrial Respiratory Chain Expression and Pancreatic Islet Cell Composition by Using a Mitochondrial DNA Mutator Mouse Model

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 333-LB
Author(s):  
XUEFEI YU ◽  
CATHERINE ARDEN ◽  
CHUN CHEN ◽  
CARLA BRADSHAW ◽  
JULIA WHITEHALL ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mouse Model ◽  
Respiratory Chain ◽  
Pancreatic Islet ◽  
Islet Cell ◽  
Mitochondrial Respiratory Chain ◽  
Pancreatic Islet Cell ◽  
Cell Composition ◽  
Mitochondrial Respiratory
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