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Severe neonatal MEG...
Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1
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- Fellman, Vineta (författare)
- Lund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,University of Helsinki,Folkhälsan Research Center
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- Banerjee, Rishi (författare)
- University of Helsinki,Folkhälsan Research Center
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- Lin, Kai Lan (författare)
- Åbo Akademi University
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- Pulli, Ilari (författare)
- Åbo Akademi University
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- Cooper, Helen (författare)
- Åbo Akademi University
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- Tyynismaa, Henna (författare)
- University of Helsinki
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- Kallijärvi, Jukka (författare)
- University of Helsinki,Folkhälsan Research Center
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(creator_code:org_t)
- Elsevier BV, 2022
- 2022
- Engelska.
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Ingår i: Biochimica et Biophysica Acta - Molecular Basis of Disease. - : Elsevier BV. - 0925-4439. ; 1868:1
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Nyckelord
- Cholesterol trafficking
- Endoplasmic reticulum
- Mitochondrial disease
- Newborn infant
- Respiratory chain
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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