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Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood

Lookup NU author(s): Dr David Lewis-Smith, Dr Helen GriffinORCiD, Dr Jennifer Duff, Dr Angela Pyle, Professor Robert Taylor, Dr Patrick Yu Wai Man, Professor Rita HorvathORCiD, Professor Patrick Chinnery

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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.

Publication metadata

Author(s): Lewis-Smith D, Kamer KJ, Griffin H, Childs AM, Pysden K, Titov D, Duff J, Pyle A, Taylor RW, Yu-Wai-Man P, Ramesh V, Horvath R, Mootha VK, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Neurology: Genetics

Year: 2016

Volume: 2

Issue: 2

Online publication date: 03/03/2016

Acceptance date: 08/01/2016

Date deposited: 06/02/2020

ISSN (electronic): 2376-7839

Publisher: AAN Publications

URL: https://doi.org/10.1212/NXG.0000000000000059

DOI: 10.1212/NXG.0000000000000059

PubMed id: 27123478

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