Ontology highlight
ABSTRACT: Objective
To define the mechanism responsible for fatigue, lethargy, and weakness in 2 cousins who had a normal muscle biopsy.Methods
Exome sequencing, long-range PCR, and Sanger sequencing to identify the pathogenic mutation. Functional analysis in the patient fibroblasts included oxygen consumption measurements, extracellular acidification studies, Western blotting, and calcium imaging, followed by overexpression of the wild-type protein.Results
Analysis of the exome sequencing depth revealed a homozygous deletion of exon 1 of MICU1 within a 2,755-base pair deletion. No MICU1 protein was detected in patient fibroblasts, which had impaired mitochondrial calcium uptake that was rescued through the overexpression of the wild-type allele.Conclusions
MICU1 mutations cause fatigue and lethargy in patients with normal mitochondrial enzyme activities in muscle. The fluctuating clinical course is likely mediated through the mitochondrial calcium uniporter, which is regulated by MICU1.
SUBMITTER: Lewis-Smith D
PROVIDER: S-EPMC4830195 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
Lewis-Smith David D Kamer Kimberli J KJ Griffin Helen H Childs Anne-Marie AM Pysden Karen K Titov Denis D Duff Jennifer J Pyle Angela A Taylor Robert W RW Yu-Wai-Man Patrick P Ramesh Venkateswaran V Horvath Rita R Mootha Vamsi K VK Chinnery Patrick F PF
Neurology. Genetics 20160303 2
<h4>Objective</h4>To define the mechanism responsible for fatigue, lethargy, and weakness in 2 cousins who had a normal muscle biopsy.<h4>Methods</h4>Exome sequencing, long-range PCR, and Sanger sequencing to identify the pathogenic mutation. Functional analysis in the patient fibroblasts included oxygen consumption measurements, extracellular acidification studies, Western blotting, and calcium imaging, followed by overexpression of the wild-type protein.<h4>Results</h4>Analysis of the exome se ...[more]