Exome sequencing identifies NFS1 deficiency in a novel Fe‐S cluster disease, infantile mitochondrial complex II/III deficiency
Abstract Iron‐sulfur (Fe‐S) clusters are a class of highly conserved and ubiquitous prosthetic groups with unique chemical properties that allow the proteins that contain them, Fe‐S proteins, to assist in various key biochemical pathways. Mutations in Fe‐S proteins often disrupt Fe‐S cluster assembl...
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doaj-1eb51256fe8f4b6ca24045e47c3b068a2020-11-25T03:08:00ZengWileyMolecular Genetics & Genomic Medicine2324-92692014-01-0121738010.1002/mgg3.46Exome sequencing identifies NFS1 deficiency in a novel Fe‐S cluster disease, infantile mitochondrial complex II/III deficiencySali M. K. Farhan0Jian Wang1John F. Robinson2Piya Lahiry3Victoria M. Siu4Chitra Prasad5Jonathan B. Kronick6David A. Ramsay7C. Anthony Rupar8Robert A. Hegele9Robarts Research Institute Schulich School of Medicine and Dentistry Western University London Ontario N6A 5K8 CanadaRobarts Research Institute Schulich School of Medicine and Dentistry Western University London Ontario N6A 5K8 CanadaRobarts Research Institute Schulich School of Medicine and Dentistry Western University London Ontario N6A 5K8 CanadaRobarts Research Institute Schulich School of Medicine and Dentistry Western University London Ontario N6A 5K8 CanadaDepartment of Biochemistry Schulich School of Medicine and Dentistry Western University London Ontario N6A 5C1 CanadaDepartment of Biochemistry Schulich School of Medicine and Dentistry Western University London Ontario N6A 5C1 CanadaDivision of Clinical and Metabolic Genetics The Hospital for Sick Children Department of Pediatrics University of Toronto Toronto Ontario M5G 1X8 CanadaDepartment of Pathology London Health Sciences Centre London Ontario N6A 5A5 CanadaDepartment of Biochemistry Schulich School of Medicine and Dentistry Western University London Ontario N6A 5C1 CanadaRobarts Research Institute Schulich School of Medicine and Dentistry Western University London Ontario N6A 5K8 CanadaAbstract Iron‐sulfur (Fe‐S) clusters are a class of highly conserved and ubiquitous prosthetic groups with unique chemical properties that allow the proteins that contain them, Fe‐S proteins, to assist in various key biochemical pathways. Mutations in Fe‐S proteins often disrupt Fe‐S cluster assembly leading to a spectrum of severe disorders such as Friedreich's ataxia or iron‐sulfur cluster assembly enzyme (ISCU) myopathy. Herein, we describe infantile mitochondrial complex II/III deficiency, a novel autosomal recessive mitochondrial disease characterized by lactic acidemia, hypotonia, respiratory chain complex II and III deficiency, multisystem organ failure and abnormal mitochondria. Through autozygosity mapping, exome sequencing, in silico analyses, population studies and functional tests, we identified c.215G>A, p.Arg72Gln in NFS1 as the likely causative mutation. We describe the first disease in man likely caused by deficiency in NFS1, a cysteine desulfurase that is implicated in respiratory chain function and iron maintenance by initiating Fe‐S cluster biosynthesis. Our results further demonstrate the importance of sufficient NFS1 expression in human physiology.https://doi.org/10.1002/mgg3.46Autozygosity mappingFe‐S proteinsmitochondrial complex deficiencyNFS1whole‐exome sequencing. |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sali M. K. Farhan Jian Wang John F. Robinson Piya Lahiry Victoria M. Siu Chitra Prasad Jonathan B. Kronick David A. Ramsay C. Anthony Rupar Robert A. Hegele |
spellingShingle |
Sali M. K. Farhan Jian Wang John F. Robinson Piya Lahiry Victoria M. Siu Chitra Prasad Jonathan B. Kronick David A. Ramsay C. Anthony Rupar Robert A. Hegele Exome sequencing identifies NFS1 deficiency in a novel Fe‐S cluster disease, infantile mitochondrial complex II/III deficiency Molecular Genetics & Genomic Medicine Autozygosity mapping Fe‐S proteins mitochondrial complex deficiency NFS1 whole‐exome sequencing. |
author_facet |
Sali M. K. Farhan Jian Wang John F. Robinson Piya Lahiry Victoria M. Siu Chitra Prasad Jonathan B. Kronick David A. Ramsay C. Anthony Rupar Robert A. Hegele |
author_sort |
Sali M. K. Farhan |
title |
Exome sequencing identifies NFS1 deficiency in a novel Fe‐S cluster disease, infantile mitochondrial complex II/III deficiency |
title_short |
Exome sequencing identifies NFS1 deficiency in a novel Fe‐S cluster disease, infantile mitochondrial complex II/III deficiency |
title_full |
Exome sequencing identifies NFS1 deficiency in a novel Fe‐S cluster disease, infantile mitochondrial complex II/III deficiency |
title_fullStr |
Exome sequencing identifies NFS1 deficiency in a novel Fe‐S cluster disease, infantile mitochondrial complex II/III deficiency |
title_full_unstemmed |
Exome sequencing identifies NFS1 deficiency in a novel Fe‐S cluster disease, infantile mitochondrial complex II/III deficiency |
title_sort |
exome sequencing identifies nfs1 deficiency in a novel fe‐s cluster disease, infantile mitochondrial complex ii/iii deficiency |
publisher |
Wiley |
series |
Molecular Genetics & Genomic Medicine |
issn |
2324-9269 |
publishDate |
2014-01-01 |
description |
Abstract Iron‐sulfur (Fe‐S) clusters are a class of highly conserved and ubiquitous prosthetic groups with unique chemical properties that allow the proteins that contain them, Fe‐S proteins, to assist in various key biochemical pathways. Mutations in Fe‐S proteins often disrupt Fe‐S cluster assembly leading to a spectrum of severe disorders such as Friedreich's ataxia or iron‐sulfur cluster assembly enzyme (ISCU) myopathy. Herein, we describe infantile mitochondrial complex II/III deficiency, a novel autosomal recessive mitochondrial disease characterized by lactic acidemia, hypotonia, respiratory chain complex II and III deficiency, multisystem organ failure and abnormal mitochondria. Through autozygosity mapping, exome sequencing, in silico analyses, population studies and functional tests, we identified c.215G>A, p.Arg72Gln in NFS1 as the likely causative mutation. We describe the first disease in man likely caused by deficiency in NFS1, a cysteine desulfurase that is implicated in respiratory chain function and iron maintenance by initiating Fe‐S cluster biosynthesis. Our results further demonstrate the importance of sufficient NFS1 expression in human physiology. |
topic |
Autozygosity mapping Fe‐S proteins mitochondrial complex deficiency NFS1 whole‐exome sequencing. |
url |
https://doi.org/10.1002/mgg3.46 |
work_keys_str_mv |
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