Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood.

Neurol Genet
Authors
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.

Year of Publication
2016
Journal
Neurol Genet
Volume
2
Issue
2
Pages
e59
Date Published
2016 Apr
DOI
10.1212/NXG.0000000000000059
PubMed ID
27123478
PubMed Central ID
PMC4830195
Links
Grant list
G0701386 / Medical Research Council / United Kingdom
G1000848 / Medical Research Council / United Kingdom
G1002570 / Medical Research Council / United Kingdom