Sze Chern Lim, Martin Friemel, Justine E. Marum, Elena J. Tucker, Damien L. Bruno, Lisa G. Riley, John Christodoulou, Edwin P. Kirk, Avihu Boneh, Christine M. DeGennaro, Michael Springer, Vamsi K. Mootha, Tracey A. Rouault, Silke Leimkühler, David R. Thorburn, Alison G. Compton
- Ironsulfur clusters (ISCs) are important prosthetic groups that define the functions of many proteins. Proteins with ISCs (called ironsulfur or FeS proteins) are present in mitochondria, the cytosol, the endoplasmic reticulum and the nucleus. They participate in various biological pathways including oxidative phosphorylation (OXPHOS), the citric acid cycle, iron homeostasis, heme biosynthesis and DNA repair. Here, we report a homozygous mutation in LYRM4 in two patients with combined OXPHOS deficiency. LYRM4 encodes the ISD11 protein, which forms a complex with, and stabilizes, the sulfur donor NFS1. The homozygous mutation (c.203GT, p.R68L) was identified via massively parallel sequencing of 1000 mitochondrial genes (MitoExome sequencing) in a patient with deficiency of complexes I, II and III in muscle and liver. These three complexes contain ISCs. Sanger sequencing identified the same mutation in his similarly affected cousin, who had a more severe phenotype and died while a neonate. Complex IV was also deficient in her skeletalIronsulfur clusters (ISCs) are important prosthetic groups that define the functions of many proteins. Proteins with ISCs (called ironsulfur or FeS proteins) are present in mitochondria, the cytosol, the endoplasmic reticulum and the nucleus. They participate in various biological pathways including oxidative phosphorylation (OXPHOS), the citric acid cycle, iron homeostasis, heme biosynthesis and DNA repair. Here, we report a homozygous mutation in LYRM4 in two patients with combined OXPHOS deficiency. LYRM4 encodes the ISD11 protein, which forms a complex with, and stabilizes, the sulfur donor NFS1. The homozygous mutation (c.203GT, p.R68L) was identified via massively parallel sequencing of 1000 mitochondrial genes (MitoExome sequencing) in a patient with deficiency of complexes I, II and III in muscle and liver. These three complexes contain ISCs. Sanger sequencing identified the same mutation in his similarly affected cousin, who had a more severe phenotype and died while a neonate. Complex IV was also deficient in her skeletal muscle. Several other FeS proteins were also affected in both patients, including the aconitases and ferrochelatase. Mutant ISD11 only partially complemented for an ISD11 deletion in yeast. Our in vitro studies showed that the l-cysteine desulfurase activity of NFS1 was barely present when co-expressed with mutant ISD11. Our findings are consistent with a defect in the early step of ISC assembly affecting a broad variety of FeS proteins. The differences in biochemical and clinical features between the two patients may relate to limited availability of cysteine in the newborn period and suggest a potential approach to therapy.…
MetadatenAuthor details: | Sze Chern Lim, Martin Friemel, Justine E. Marum, Elena J. Tucker, Damien L. Bruno, Lisa G. Riley, John Christodoulou, Edwin P. Kirk, Avihu Boneh, Christine M. DeGennaro, Michael Springer, Vamsi K. Mootha, Tracey A. Rouault, Silke LeimkühlerORCiDGND, David R. Thorburn, Alison G. Compton |
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DOI: | https://doi.org/10.1093/hmg/ddt295 |
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ISSN: | 0964-6906 |
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ISSN: | 1460-2083 |
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Title of parent work (English): | Human molecular genetics |
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Publisher: | Oxford Univ. Press |
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Place of publishing: | Oxford |
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Publication type: | Article |
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Language: | English |
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Year of first publication: | 2013 |
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Publication year: | 2013 |
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Release date: | 2017/03/26 |
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Volume: | 22 |
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Issue: | 22 |
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Number of pages: | 14 |
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First page: | 4460 |
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Last Page: | 4473 |
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Funding institution: | NHLBI Lung GO Sequencing Project [HL-102923]; NHLBI WHI Sequencing
Project [HL-102924]; NHLBI Broad GO Sequencing Project [HL-102925];
NHLBI Seattle GO Sequencing Project [HL-102926]; NHLBI Heart GO
Sequencing Project [HL-103010]; NHLBI Melbourne Research Scholarship;
NHLBI Australian National Health and Medical Research Council; NHLBI
Victorian Government; NHLBI Eunice Kennedy Shriver National Institute of
Child Health and Human Development; NHLBI Deutsche
Forschungsgemeinschaft |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
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Peer review: | Referiert |
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