Alternative titles; symbols
HGNC Approved Gene Symbol: NFS1
Cytogenetic location: 20q11.22 Genomic coordinates (GRCh38): 20:35,668,052-35,699,352 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.22 | Combined oxidative phosphorylation deficiency 52 | 619386 | Autosomal recessive | 3 |
Iron-sulfur (Fe-S) clusters are prosthetic groups found in respiratory chain complexes and numerous mitochondrial and cytosolic enzymes. Assembly of Fe-S clusters requires cysteine desulfurases, such as NFS1, as well as scaffold proteins, iron donors, and chaperones (Li et al., 2006).
Using sequence homology to bacterial NifS, Land and Rouault (1998) cloned the human homolog of NifS, a cysteine desulfurase that is proposed to supply the inorganic sulfur in iron-sulfur clusters. In human cells, different forms of NIFS that localize either to mitochondria or to the cytosol and nucleus are synthesized from a single transcript through initiation at alternative in-frame AUGs, and initiation site selection varies according to the pH of the medium or cytosol. Thus, this form of translational regulation permits rapid redistribution of NIFS proteins into different compartments of the cell in response to changes in metabolic status.
Gross (2018) mapped the NFS1 gene to chromosome 20q11.22 based on an alignment of the NFS1 sequence (GenBank AF097025) with the genomic sequence (GRCh38).
Li et al. (2006) overexpressed the cytosolic isoform of human ISCS in yeast and showed that it was an active cysteine desulfurase that converted cysteine to alanine and covalently bound sulfur in a persulfide. Cytosolic ISCS homodimerized and formed a complex in vitro with overexpressed human cytosolic ISCU (611911). When incubated with iron regulatory protein-1 (IRP1, or ACO1; 100880), cysteine, and iron, the cytosolic isoforms of ISCS and ISCU facilitated efficient formation of a 4Fe-4S cluster on IRP1.
Using loss-of-function screening based on RNA interference, Alvarez et al. (2017) showed that environmental oxygen levels are a major driver of differential essentiality between in vitro model systems and in vivo tumors. Alvarez et al. (2017) found that, above the 3 to 8% oxygen concentration typical of most tissues, cancer cells depend on high levels of the iron-sulfur cluster biosynthetic enzyme NFS1. Mammary or subcutaneous tumors grew despite suppression of NFS1, whereas metastatic or primary lung tumors did not. Consistent with a role in surviving the high oxygen environment of incipient lung tumors, NFS1 lies in a region of genomic amplification present in lung adenocarcinoma and is most highly expressed in well-differentiated adenocarcinomas. Alvarez et al. (2017) showed that NFS1 activity is particularly important for maintaining the iron-sulfur cofactors present in multiple cell-essential proteins upon exposure to oxygen compared to other forms of oxidative damage. Furthermore, insufficient iron-sulfur cluster maintenance robustly activated the iron-starvation response and, in combination with inhibition of glutathione biosynthesis, triggered ferroptosis, a nonapoptotic form of cell death. Suppression of NFS1 cooperated with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumor growth. Alvarez et al. (2017) concluded that lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage.
Using RNAi, Biederbick et al. (2006) depleted expression of NFS1 in HeLa cells, which resulted in abnormal mitochondrial morphology, growth retardation, and decreased activity of both mitochondrial and cytoplasmic iron-sulfur cluster proteins. These abnormalities were corrected with introduction of murine Nfs1. When murine Nfs1 lacking the mitochondrial targeting presequence was introduced to the NFS1-depleted HeLa cells, these abnormalities were not fully corrected and the truncated murine Nfs1 mislocalized to the nucleus and cytoplasm. Biederbick et al. (2006) concluded that mitochondrial-localized NFS1 is required for maturation of both mitochondrial and cytoplasmic iron-sulfur proteins.
In 3 sibs from a consanguineous Old Order Mennonite family with COXPD52, Farhan et al. (2014) identified a homozygous missense mutation in the NFS1 gene (R72Q; 603485.0001). The mutation, which was found by autozygosity mapping and whole-exome sequencing, segregated with disease in the family. Reduced NFS1 transcript and protein levels were demonstrated in patient fibroblasts. Deficient respiratory chain complex II and III enzyme function was seen in patient liver and muscle tissue from 2 of the sibs.
In 3 sibs from a consanguineous Arab Christian family with COXPD52, Hershkovitz et al. (2021) identified homozygosity for the R72Q mutation in the NFS1 gene. Haplotype analysis failed to show a shared haplotype between this family and the Old Order Mennonite family reported by Farhan et al. (2014), indicating the likelihood of 2 independent mutation events. Molecular modeling suggested that the R72Q mutation may hinder NFS1-ISD11 (613311) complex formation.
In 3 sibs from a consanguineous Old Order Mennonite family with combined oxidative phosphorylation deficiency-52 (COXPD52; 619386), Farhan et al. (2014) identified homozygosity for a c.215G-A transition (c.215G-A, NM_021100.4) in the NFS1 gene, resulting in an arg72-to-gln (R72Q) substitution at a highly conserved residue involved in the Fe-S cluster assembly machinery. The mutation, which was found by autozygosity mapping and whole-exome sequencing, segregated with disease in the family. The mutation was absent in 40 Old Order Mennonite controls and was identified in heterozygous state in 1 of 3,033 ethnically diverse controls. Reduced NFS1 transcript and protein levels were demonstrated in patient fibroblasts. Deficient respiratory chain complex II and III enzyme function was seen in patient liver and muscle tissue from 2 of the sibs.
In 3 sibs from a consanguineous Arab Christian family with COXPD52, Hershkovitz et al. (2021) identified homozygosity for the R72Q mutation in the NFS1 gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. The mutation had a minor allele frequency of 0.00006 in the gnomAD database, 0.0002 in the ESP 6500 database, and 0.000081, including one homozygous individual, in the RGC database. Haplotype analysis failed to show a shared haplotype between this family and the Old Order Mennonite family reported by Farhan et al. (2014), indicating the likelihood of 2 independent mutation events. Molecular modeling suggested that the R72Q mutation may hinder NFS1-ISD11 (613311) complex formation.
Alvarez, S. W., Sviderskiy, V. O., Terzi, E. M., Papagiannakopoulos, T., Moreira, A. L., Adams, S., Sabatini, D. M., Birsoy, K., Possemato, R. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551: 639-643, 2017. Note: Erratum: Nature 609: E12, 2022. [PubMed: 29168506] [Full Text: https://doi.org/10.1038/nature24637]
Biederbick, A., Stehling, O., Rosser, R., Niggemeyer, B., Nakai, Y., Elsasser, H.-P., Lill, R. Role of human mitochondrial Nfs1 in cytosolic iron-sulfur protein biogenesis and iron regulation. Molec. Cell. Biol. 26: 5675-5687, 2006. [PubMed: 16847322] [Full Text: https://doi.org/10.1128/MCB.00112-06]
Farhan, S. M. K., Wang, J., Robinson, J. F., Lahiry P., Siu, V. M., Prasad, C., Kronick, J. B., Ramsay, D. A., Rupar C. A., Hegele, R. A. Exome sequencing identifies NFS1 deficiency in a novel Fe-S cluster disease, infantile mitochondrial complex II/III deficiency. Molec. Genet. Genomic Med. 2: 73-80, 2014. [PubMed: 24498631] [Full Text: https://doi.org/10.1002/mgg3.46]
Gross, M. B. Personal Communication. Baltimore, Md. 2/23/2018.
Hershkovitz, T., Kurolap, A., Tal, G., Paperna, T., Mory, A., Staples, J., Brigatti K. W., Regeneron Genetics Center, Gonzaga-Jauregui, C., Dumin, E., Saada, A., Mandel, H., Feldman, H. B. A recurring NFS1 pathogenic variant causes a mitochondrial disorder with variable intra-familial patient outcomes. Molec. Genet. Metab. Rep. 26: 100699, 2021. [PubMed: 33457206] [Full Text: https://doi.org/10.1016/j.ymgmr.2020.100699]
Land, T., Rouault, T. A. Targeting of a human iron-sulfur cluster assembly enzyme, nifs, to different subcellular compartments is regulated through alternative AUG utilization. Molec. Cell 2: 807-815, 1998. [PubMed: 9885568] [Full Text: https://doi.org/10.1016/s1097-2765(00)80295-6]
Li, K., Tong, W.-H., Hughes, R. M., Rouault, T. A. Roles of the mammalian cytosolic cysteine desulfurases, ISCS, and scaffold protein, ISCU, in iron-sulfur cluster assembly. J. Biol. Chem. 281: 12344-12351, 2006. [PubMed: 16527810] [Full Text: https://doi.org/10.1074/jbc.M600582200]