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Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1.
- Source :
-
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2022 Jan 01; Vol. 1868 (1), pp. 166298. Date of Electronic Publication: 2021 Oct 28. - Publication Year :
- 2022
-
Abstract
- In the diagnostic work-up of a newborn infant with a metabolic crisis, lethal multiorgan failure on day six of life, and increased excretion of 3-methylglutaconic acid, we found using whole genome sequencing a homozygous SERAC1 mutation indicating MEGDHEL syndrome (3-methylglutaconic aciduria with deafness-dystonia, hepatopathy, encephalopathy, and Leigh-like syndrome). The SERAC1 protein is located at the contact site between mitochondria and the endoplasmic reticulum (ER) and is crucial for cholesterol trafficking. Our aim was to investigate the effect of the homozygous truncating mutation on mitochondrial structure and function. In the patient fibroblasts, no SERAC1 protein was detected, the mitochondrial network was severely fragmented, and the cristae morphology was altered. Filipin staining showed uneven localization of unesterified cholesterol. The calcium buffer function between cytoplasm and mitochondria was deficient. In liver mitochondria, complexes I, III, and IV were clearly decreased. In transfected COS-1 cells the mutant protein with the a 45-amino acid C-terminal truncation was distributed throughout the cell, whereas wild-type SERAC1 partially colocalized with the mitochondrial marker MT-CO1. The structural and functional mitochondrial abnormalities, caused by the loss of SERAC1, suggest that the crucial disease mechanism is disrupted interplay between the ER and mitochondria leading to decreased influx of calcium to mitochondria and secondary respiratory chain deficiency.<br /> (Copyright © 2021. Published by Elsevier B.V.)
- Subjects :
- Calcium metabolism
Cholesterol metabolism
Endoplasmic Reticulum genetics
Endoplasmic Reticulum metabolism
Female
Glutarates metabolism
Humans
Infant, Newborn
Male
Metabolism, Inborn Errors metabolism
Metabolism, Inborn Errors pathology
Mitochondria, Liver metabolism
Mitochondria, Liver pathology
Mitochondrial Diseases metabolism
Mitochondrial Diseases pathology
Whole Genome Sequencing
Carboxylic Ester Hydrolases genetics
Metabolism, Inborn Errors genetics
Mitochondria, Liver genetics
Mitochondrial Diseases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1879-260X
- Volume :
- 1868
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Publication Type :
- Academic Journal
- Accession number :
- 34751152
- Full Text :
- https://doi.org/10.1016/j.bbadis.2021.166298