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Expanding the phenotypic and biochemical spectrum of NDUFAF3-related mitochondrial disease

Recessive variants in NDUFAF3 are a known cause of complex I (CI)-related mitochondrial disorders (MDs). The seven patients reported to date exhibited severe neurologic symptoms and lactic acidosis, followed by a fatal course and death during infancy in most cases. We present a 10-year-old patient w...

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Main Authors: Ven, Amelie T. van der (Author) , Cabrera-Orefice, Alfredo (Author) , Wente, Isabell (Author) , Feichtinger, René G. (Author) , Tsiakas, Konstantinos (Author) , Weiss, Deike (Author) , Bierhals, Tatjana (Author) , Scholle, Leila (Author) , Prokisch, Holger (Author) , Kopajtich, Robert (Author) , Santer, René (Author) , Mayr, Johannes A. (Author) , Hempel, Maja (Author) , Wittig, Ilka (Author)
Format: Article (Journal)
Language:English
Published: 10 August 2023
In: Molecular genetics and metabolism
Year: 2023, Volume: 140, Issue: 3, Pages: 1-8
ISSN:1096-7206
DOI:10.1016/j.ymgme.2023.107675
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ymgme.2023.107675
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1096719223003050
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Author Notes:Amelie T. van der Ven, Alfredo Cabrera-Orefice, Isabell Wente, René G. Feichtinger, Konstantinos Tsiakas, Deike Weiss, Tatjana Bierhals, Leila Scholle, Holger Prokisch, Robert Kopajtich, René Santer, Johannes A. Mayr, Maja Hempel, Ilka Wittig
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Summary:Recessive variants in NDUFAF3 are a known cause of complex I (CI)-related mitochondrial disorders (MDs). The seven patients reported to date exhibited severe neurologic symptoms and lactic acidosis, followed by a fatal course and death during infancy in most cases. We present a 10-year-old patient with a neurodevelopmental disorder, progressive exercise intolerance, dystonia, basal ganglia abnormalities, and elevated lactate concentration in blood. Trio-exome sequencing revealed compound-heterozygosity for a pathogenic splice-site and a likely pathogenic missense variant in NDUFAF3. Spectrophotometric analysis of fibroblast-derived mitochondria demonstrated a relatively mild reduction of CI activity. Complexome analyses revealed severely reduced NDUFAF3 as well as CI in patient fibroblasts. Accumulation of early sub-assemblies of the membrane arm of CI associated with mitochondrial complex I intermediate assembly (MCIA) complex was observed. The most striking additional findings were both the unusual occurrence of free monomeric CI holding MCIA and other assembly factors. Here we discuss our patient in context of genotype, phenotype and metabolite data from previously reported NDUFAF3 cases. With the atypical presentation of our patient, we provide further insight into the phenotypic spectrum of NDUFAF3-related MDs. Complexome analysis in our patient confirms the previously defined role of NDUFAF3 within CI biogenesis, yet adds new aspects regarding the correct timing of both the association of soluble and membrane arm modules and CI-maturation as well as respiratory supercomplex formation.
Item Description:Online verfügbar 4 August 2023, Version des Artikels 10 August 2023
Gesehen am 18.10.2023
Physical Description:Online Resource
ISSN:1096-7206
DOI:10.1016/j.ymgme.2023.107675

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