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Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1

Fellman, Vineta LU orcid ; Banerjee, Rishi ; Lin, Kai Lan ; Pulli, Ilari ; Cooper, Helen ; Tyynismaa, Henna and Kallijärvi, Jukka LU (2022) In Biochimica et Biophysica Acta - Molecular Basis of Disease 1868(1).
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... (More)

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.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cholesterol trafficking, Endoplasmic reticulum, Mitochondrial disease, Newborn infant, Respiratory chain
in
Biochimica et Biophysica Acta - Molecular Basis of Disease
volume
1868
issue
1
article number
166298
publisher
Elsevier
external identifiers
  • pmid:34751152
  • scopus:85118593330
ISSN
0925-4439
DOI
10.1016/j.bbadis.2021.166298
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2021
id
2f875cb5-8619-4b1e-aeb7-f7458da8451d
date added to LUP
2021-11-24 08:59:56
date last changed
2024-06-15 21:30:52
@article{2f875cb5-8619-4b1e-aeb7-f7458da8451d,
  abstract     = {{<p>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.</p>}},
  author       = {{Fellman, Vineta and Banerjee, Rishi and Lin, Kai Lan and Pulli, Ilari and Cooper, Helen and Tyynismaa, Henna and Kallijärvi, Jukka}},
  issn         = {{0925-4439}},
  keywords     = {{Cholesterol trafficking; Endoplasmic reticulum; Mitochondrial disease; Newborn infant; Respiratory chain}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  publisher    = {{Elsevier}},
  series       = {{Biochimica et Biophysica Acta - Molecular Basis of Disease}},
  title        = {{Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1}},
  url          = {{http://dx.doi.org/10.1016/j.bbadis.2021.166298}},
  doi          = {{10.1016/j.bbadis.2021.166298}},
  volume       = {{1868}},
  year         = {{2022}},
}