RT Journal Article
SR Electronic
T1 Homozygous deletion in <em>MICU1</em> presenting with fatigue and lethargy in childhood
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams &amp; Wilkins
SP e59
DO 10.1212/NXG.0000000000000059
VO 2
IS 2
A1 Lewis-Smith, David
A1 Kamer, Kimberli J.
A1 Griffin, Helen
A1 Childs, Anne-Marie
A1 Pysden, Karen
A1 Titov, Denis
A1 Duff, Jennifer
A1 Pyle, Angela
A1 Taylor, Robert W.
A1 Yu-Wai-Man, Patrick
A1 Ramesh, Venkateswaran
A1 Horvath, Rita
A1 Mootha, Vamsi K.
A1 Chinnery, Patrick F.
YR 2016
UL http://ng.neurology.org/content/2/2/e59.abstract
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