Alternative titles; symbols
HGNC Approved Gene Symbol: ISCA1
SNOMEDCT: 1279890001;
Cytogenetic location: 9q21.33 Genomic coordinates (GRCh38) : 9:86,264,546-86,282,538 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q21.33 | Multiple mitochondrial dysfunctions syndrome 5 | 617613 | Autosomal recessive | 3 |
ISCA1, like IBA57 (615316) and ISCA2 (615317), is part of the iron-sulfur cluster (ISC) assembly machinery in mitochondria. These 3 proteins function late in the biosynthetic pathway of mitochondrial 4Fe-4S proteins (Sheftel et al., 2012).
By immunoscreening a human brain cDNA expression library with serum from a patient with Sjogren syndrome (270150), followed by database analysis, Cozar-Castellano et al. (2004) cloned ISCA1, which they called HBLD2. The deduced 129-amino acid protein has a predicted molecular mass of 15.5 kD and shares 97% amino acid identity with its rat ortholog. ISCA1 has a conserved C-terminal HESB domain, and the 5-prime untranslated region contains an SP1 binding site. Northern blot analysis detected a 2.8-kb transcript with high expression in cerebellum and kidney and lower expression in heart and liver. Immunocytochemistry studies localized ISCA1 to mitochondria when expressed in rat neuroblastoma cells.
Using a computational screen to identify human and mouse genes encoding mitochondrial proteins involved in heme biosynthesis, Nilsson et al. (2009) identified ISCA1.
Using cell fractionation, immunoblot analysis, and confocal microscopy, Sheftel et al. (2012) demonstrated mitochondrial localization of human ISCA1.
Cozar-Castellano et al. (2004) showed that expression of ISCA1 functionally complemented an Isa1-null mutant yeast strain, suggesting that ISCA1 likely plays a role in biogenesis of mitochondrial iron-sulfur clusters.
Using a yeast 2-hybrid screen of a human kidney cDNA library to identify IOP1 (NARFL; 611118)-interacting proteins, Song et al. (2009) identified ISCA1. Immunoprecipitation analysis showed that the interaction required 3 conserved cysteines in ISCA1 predicted to be involved in binding iron/sulfur clusters. Western blot analysis revealed mitochondrial expression of ISCA1, as well as reduced cytosolic expression. Small interfering RNA-mediated knockdown of ISCA1 in HeLa cells resulted in decreased activity of 2 mitochondrial iron-sulfur enzymes, succinate dehydrogenase (see 600857) and aconitase (ACO2; 100850), as well the cytosolic iron-sulfur enzyme aconitase (ACO1; 100880). Song et al. (2009) proposed that ISCA1 is important in both mitochondrial and cytosolic iron-sulfur biogenesis and that the cytosolic activity is affected by its interaction with IOP1.
Sheftel et al. (2012) used RNA interference to deplete HeLa cells of ISCA1, ISCA2, and IBA57 and observed swollen mitochondria devoid of cristae membranes. Depletion of these proteins also resulted in diminished activities of mitochondrial 4Fe-4S proteins, including aconitase, respiratory complex I (see 602985), and lipoic acid synthase (LIAS; 607031). In contrast, cellular heme content and mitochondrial 2Fe-2S ferrochelatase (FECH; 612386) were unaffected. Sheftel et al. (2012) proposed that ISCA1, ISCA2, and IBA57 are specifically involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the ISC assembly pathway.
Cozar-Castellano et al. (2004) determined that the ISCA1 gene contains 4 exons.
By genomic sequence analysis, Cozar-Castellano et al. (2004) mapped the ISCA1 gene to chromosome 9q21.2-q22.1.
In 2 unrelated, deceased probands of Indian descent with multiple mitochondrial dysfunctions syndrome-5 (MMDS5; 617613), Shukla et al. (2017) identified a homozygous missense mutation in the ISCA1 gene (E87K; 611006.0001). Molecular modeling predicted that the mutation would lead to destabilization of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Haplotype analysis suggested a founder effect. Functional studies of the variant and studies of patient cells were not performed.
In an Italian boy with MMDS5, Torraco et al. (2018) identified a homozygous missense mutation (V10G; 611006.0002) in the ISCA1 gene. The mutation was detected by next-generation sequencing of a mitochondrial-targeted gene panel and confirmed by Sanger sequencing. Both parents and an unaffected sib were heterozygous for the mutation.
Nilsson et al. (2009) found that targeted knockdown of Isca1 in zebrafish resulted in profound anemia.
In 2 unrelated probands of Indian descent with multiple mitochondrial dysfunctions syndrome-5 (MMDS5; 617613), Shukla et al. (2017) identified a homozygous c.259G-A transition (c.259G-A, NM_030940.3) in exon 4 of the ISCA1 gene, resulting in a glu87-to-lys (E87K) substitution at a conserved residue in the Fe-S biogenesis domain. Molecular modeling predicted that the mutation would lead to destabilization of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutation was not found in homozygous state in the 1000 Genomes Project or the Exome Variant Server databases or in an in-house exome database of 139 individuals from the same population; however, the variant was found at very low frequencies in heterozygous state in the ExAC and gnomAD databases. Both probands had a similarly affected sib, although biologic material was not available from the sibs. All of the children were deceased at the time of the report. Haplotype analysis suggested a founder effect. Functional studies of the variant and studies of patient cells were not performed.
In an Italian boy with multiple mitochondrial dysfunctions syndrome-5 (MMDS5; 617613), Torraco et al. (2018) identified a homozygous c.29T-G transversion (c.29T-G, NM_030940.3) in exon 1 of the ISCA1 gene, resulting in a val10-to-gly (V10G) substitution at a moderately conserved residue predicted to be located in the presequence part of the protein. The mutation was detected by next-generation sequencing of a mitochondrial-targeted gene panel and confirmed by Sanger sequencing. The parents were heterozygous for the mutation. An older sib died at 1 year of age with clinical features of MMDS5, but molecular testing was not performed. The mutation was not present in the dbSNP, ExAC, and EVS databases. Postmortem brain and muscle tissue from the patient had multiple defects of respiratory chain complex activities. Studies in patient fibroblasts showed reduction of ISCA1 protein content, reduction of the [4Fe-4S] cluster-containing proteins NDUFS1 (157655) and SDHB (185470), and reduction in ATP synthesis with succinate, malate, and pyruvate as substrates. Functional analysis of the ISCA1 protein containing the V10G mutation in HeLa cells showed decreased mitochondrial ISCA1 protein import, stability, and biologic function in the mitochondrial matrix.
Cozar-Castellano, I., del Valle Machargo, M., Trujillo, E., Arteaga, M. F., Gonzalez, T., Martin-Vasallo, P., Avila, J. hIscA: a protein implicated in the biogenesis of iron-sulfur clusters. Biochim. Biophys. Acta 1700: 179-188, 2004. [PubMed: 15262227] [Full Text: https://doi.org/10.1016/j.bbapap.2004.05.004]
Nilsson, R., Schultz, I. J., Pierce, E. L., Soltis, K. A., Naranuntarat, A., Ward, D. M., Baughman, J. M., Paradkar, P. N., Kingsley, P. D., Culotta, V. C., Kaplan, J., Palis, J., Paw, B. H., Mootha, V. K. Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis. Cell Metab. 10: 119-130, 2009. [PubMed: 19656490] [Full Text: https://doi.org/10.1016/j.cmet.2009.06.012]
Sheftel, A. D., Wilbrecht, C., Stehling, O., Niggemeyer, B., Elsasser, H.-P., Muhlenhoff, U., Lill, R. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation. Molec. Biol. Cell 23: 1157-1166, 2012. [PubMed: 22323289] [Full Text: https://doi.org/10.1091/mbc.E11-09-0772]
Shukla, A., Hebbar, M., Srivastava, A., Kadavigere, R., Upadhyai, P., Kanthi, A., Brandau, O., Bielas, S., Girisha, K. M. Homozygous p.(Glu8Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome. J. Hum. Genet. 62: 723-727, 2017. [PubMed: 28356563] [Full Text: https://doi.org/10.1038/jhg.2017.35]
Song, D., Tu, Z., Lee, F. S. Human ISCA1 interacts with IOP1/NARFL and functions in both cytosolic and mitochondrial iron-sulfur protein biogenesis. J. Biol. Chem. 284: 35297-35307, 2009. [PubMed: 19864422] [Full Text: https://doi.org/10.1074/jbc.M109.040014]
Torraco, A., Stehling, O., Stumpfig, C., Rosser, R., De Rasmo, D., Fiermonte, G., Verrigni, D., Rizza, T., Vozza, A., Di Nottia, M., Diodato, D., Martinelli, D., Piemonte, F., Dionisi-Vici, C., Bertini, E., Lill, R., Carrozzo, R. ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins. Hum. Molec. Genet. 27: 2739-2754, 2018. [PubMed: 29767723] [Full Text: https://doi.org/10.1093/hmg/ddy183]