PT  - JOURNAL ARTICLE
AU  - Lewis-Smith, David
AU  - Kamer, Kimberli J.
AU  - Griffin, Helen
AU  - Childs, Anne-Marie
AU  - Pysden, Karen
AU  - Titov, Denis
AU  - Duff, Jennifer
AU  - Pyle, Angela
AU  - Taylor, Robert W.
AU  - Yu-Wai-Man, Patrick
AU  - Ramesh, Venkateswaran
AU  - Horvath, Rita
AU  - Mootha, Vamsi K.
AU  - Chinnery, Patrick F.
TI  - Homozygous deletion in <em>MICU1</em> presenting with fatigue and lethargy in childhood
AID  - 10.1212/NXG.0000000000000059
DP  - 2016 Apr 01
TA  - Neurology Genetics
PG  - e59
VI  - 2
IP  - 2
4099  - http://ng.neurology.org/content/2/2/e59.short
4100  - http://ng.neurology.org/content/2/2/e59.full
SO  - Neurol Genet2016 Apr 01; 2
AB  - 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.CK=creatine kinase; GATK=Genome Analysis Toolkit; MAF=minor allele frequency; PDH=pyruvate dehydrogenase; SNVs=single nucleotide variants